Amino Alcohol Derivatives And Their Use As Renin Inhibitor

ABSTRACT

The application relates to novel amino alcohols of the general formula (I) where R, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  each have the definitions illustrated in detail in the description, to a process for their preparation and to the use of these compounds as medicines, in particular as renin inhibitors.

The invention relates to novel amino alcohols, to processes forpreparing the inventive compounds, to pharmaceutical preparationscomprising them and to their use as medicaments, in particular as renininhibitors.

Amino-compounds showing renin-inhibiting properties are known, forexample from EP519433.

Firstly, the present invention provides compounds of the general formula

where

R₁ is a) hydrogen, amino or hydroxyl; or

-   -   is b) C₁-C₈-alkyl, C₃-C₈-cyloalkyl, C₁-C₈-alkanoyl,        C₁-C₈-alkoxycarbonyl, aryl-C₀-C₄-alkyl or        heterocyclyl-C₀-C₄-alkyl, which radicals may be substituted by        1-4, C₁-C₈-alkyl, halogen, cyano, oxide, oxo, trifluoromethyl,        C₁-C₈-alkoxy, C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl; R₂        is a) C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkylsulphonyl,        C₃-C₈-cyloalkylsulphonyl, aryl-C₀-C₈-alkylsulphonyl,        heterocyclylsulphonyl, C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl,        aryl-C₁-C₈-alkanoyl, aryl-C₃-C₈-cycloalkanoyl, C₁-C₈-alkanoyl,        C₁-C₈-alkoxycarbonyl, optionally N-mono- or        N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, aryl-C₀-C₄-alkyl        or heterocyclyl-C₀-C₄-alkyl, which radicals may be substituted        by 1-4 C₁-C₈-alkyl, C₃-C₁₂-cycloalkyl, C₃-C₈-cycloalkoxy, amino,        C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkanoylamino,        C₁-C₆-alkoxycarbonylamino, halogen, oxo, cyano, hydroxyl, oxide,        trifluoromethyl, C₁-C₈-alkoxy, optionally N-mono- or        N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, optionally        esterified carboxyl, C₁-C₆-alkylenedioxy, aryl or heterocyclyl;        or

is b) together with R₁ and the nitrogen atom to which they are bonded asaturated or partly unsaturated 4-8-membered heterocyclic ring which maycontain an additional nitrogen, oxygen or sulphur atom or a —SO— or—SO2-group, in which case the additional nitrogen atom may optionally besubstituted by C₁-C₈-alkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, arylor heterocyclyl radicals, and this heterocyclic ring may be part of abicyclic or tricyclic ring system having a total of up to 16 members andthe second ring may also contain a nitrogen, oxygen or sulphur atom or a—SO— or —SO2-group, and the nitrogen atom in the second ring mayoptionally be substituted by C₁-C₈-alkyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl radicals and all ring systemsmentioned may be substituted by 1-4 C₁-C₈-alkyl, C₃-C₈-cyloalkyl,C₁-C₈-alkylsulphonyl, C₃-C₈-cycloalkylsulphonyl,aryl-C₀-C₈-alkylsulphonyl, heterocyclylsulphonyl,C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl, aryl-C₁-C₈-alkanoyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, optionally N-mono- or N,N-di-C₁-C₈-alkylatedcarbamoyl-C₀-C₈-alkyl, halogen, hydroxyl, oxide, oxo, trifluoromethyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,C₁-C₈-alkoxycarbonylamino, C₁-C₈-alkanoylamino, C₁-C₈-alkyl-amino,N,N-di-C₁-C₈-alkylamino, aryl-C₀-C₄-alkyl, aryloxy-C₀-C₄-alkyl,aryl-C₀-C₄-alkyl-C₁-C₈-alkoxy, aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy,heterocyclyl-CC₀-C₄-alkyl, heterocyclyloxy-C₀-C₄-alkyl,heterocyclyl-C₀-C₄-alkyl-C₁-C₈-alkoxy orheterocyclyloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy;

R₃ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl;

R₄ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl;

R₆ are each independently hydrogen or C₁-C₈-alkyl or, together with thecarbon atom to which they are bonded, are a C₀-C₈-cycloalkylideneradical;

R₆ is one oxygen atom or two hydrogen atoms;

R is optionally suited arylamino, N-aryl-N-(lower alkoxy)(loweralkyl))amino, N-aryl-N-aryl(lower alkyl)amino or heterocyclyl bonded viaa ring nitrogen atom;

and salts thereof.

The asymmetric carbon atoms present in compounds of the formula (I) mayhave R—, S— or R,S-configurations. Accordingly, the compounds presentmay occur as isomer mixtures or as pure isomers, in particular asdiastereoisomer mixtures, enantiomer pairs or pure enantiomers.

In the context of the restrictions specified for the substituents of theformula (I), the individual substituents are defined as follows:

Aryl, and aryl in arylamino, aryl-C₀-C₄-alkyl, aryl(lower alkyl),N-aryl-N-(lower alkoxy)(lower alkyl)amino, N-aryl-N-aryl(loweralkyl)amino, contains generally 1-14, preferably 6-10 carbon atoms, andis, for example, phenyl, indenyl, e.g. 2- or 4-indenyl, or naphthyl,e.g. 1- or 2-naphthyl. Preference is given to aryl having 6-10 carbonatoms, in particular phenyl or 1- or 2-naphthyl. The radicals mentionedmay be unsubstituted or, for example, mono- or polysubstituted, forexample mono- or disubstituted, by a lower alkyl, hydroxyl, loweralkoxy, oxo, carbamoyl(lower alkoxy), C₃-C₈-cycloalkyl,C₁-C₈-alkylsulphonyl, C₃-C₈-cycloalkylsulphonyl,aryl-C₀-C₀-alkylsulphonyl, heterocyclylsulphonyl,C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl, aryl-C₁-C₈-alkanoyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, optionally N-mono- or N,N-di-C₁-C₈-alkylatedcarbamoyl-C₁-C₈-alkyl, (lower alkyl) carbamoyl(lower alkoxy), di(loweralkyl) carbamoyl(lower alkoxy), amino, (lower alkyl)- or di(loweralkyl)amino, carboxyl, (lower alkoxy)carbonyl, carbamoyl, sulphamoyl,(lower alkane)sulphonyl, halogen, trifluoromethyl, nitro, phenyl, 5- or6-membered heterocyclyl containing as a heteroatom 1 nitrogen, sulphuror oxygen atom, 2 nitrogen atoms, 1 nitrogen atom and 1 sulphur atom, or1 nitrogen atom and 1 oxygen atom, such as pyridyl, and/or by cyano, andthe substituent may be present in any position, for example the o-, m-or p-position of the phenyl radicals, or in the 3- or 4-position of the1- or 2-naphthyl radical, and a plurality of identical or differentsubstituents may also be present.

Arylamino is, for example, anilino or 1- or 2-naphthylamino which areeach unsubstituted or substituted in the phenyl or naphthyl moiety asspecified above.

Heterocyclyl, and heterocyclyl in heterocyclyl-C₀-C₄-alkyl has, forexample, from 5 to 7 ring atoms in the heterocyclyl ring and may containone ring nitrogen atom and/or one further ring heteroatom selected fromoxygen, sulphur and nitrogen, is, for example, furanyl,tetrahydrofuranyl, pyranyl, tetrahydropyranyl, thiazolyl, oxazolyl,pyridinyl or imidazolyl which are each unsubstituted or substituted byC₁-C₈-alkyl, halogen, oxo, oxide, cyano, trifluoromethyl, C₁-C₈-alkoxy,C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl.

Heterocyclyl-C₀-C₄-alkyl is, for example, pyridinyl, methylenepyridinylor imidazolyl.

In the case of nitrogen heterocycles, the heterocyclyl radicals can bebonded either via the nitrogen or via a ring carbon.

Heterocyclyl bonded via a ring nitrogen atom and having from 4 to 8 ringatoms has in particular from 5 to 7 ring atoms and may have 1 or 2fused-on phenyl or cycloalkyl radicals, or else be present as a spirocompound. Examples include pyrrolidino, piperidino, piperazine,morpholino, thiomorpholino, indolin-1-yl, isoindolin-2-yl,2,3-dihydrobenzimidazol-1-yl, 1,2,3,4-tetrahydroquinol-1-yl,1,2,3,4-tetrahydroisoquinol-2-yl,1,2,3,4-tetrahydro-1,3-benzodiazin-1-yl or -3-yl,1,2,3,4-tetrahydro-1,4-benzodiazin-1-yl,3,4-dihydro-2H-1,4-benzoxazin-4-yl,3,4-dihydro-2H-1,4-benzothiazin-4-yl,3,4-dihydro-2H-1,3-benzothiazin-1-yl,3,4,5,6,7,8-hexahydro-2H-1,4benzoxazin-4-yl,3,4,5,6,7,8-hexahydro-2H-1,4-benzothiazin-4-yl,2,3,4,5-tetrahydro-1H-1-benz[6,7-b]azepin-1-yl and5,6-dihydrophenanthridin-5-yl. Preference is given to benzofused 5- to7-membered aza-, diaza-, azoxa- and azathiacycloalkenyl radicals bondedvia a nitrogen atom, in particular indolin-1-yl,1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl,1,2,3,4-tethydro-1,3-benzodiazin-1-yl,1,2,3,4-tetrahydro-1,4-benzodiazin-1-yl,3,4-dihydro-2H-1,4-benzoxazin-4-yl,3,4-dihydro-2H-1,4-benzothiazin-4-yl,3,4-dihydro-2H-1,3-benzothiazin-1-yl and2,3,4,5-tetrahydro-1H-1-benz[6,7-b]azepin-1-yl. Further preferred for—NR₁R₂ are in particular pyrrolidino, piperidino, morpholino,9-azabicyclo[3.3.1]non-9-yl, 1-azepan-1-yl, 2,8-diazaspiro[4.5dec-8-yl,octahydroisoindol-2-yl, 4-azatricyclo[5.2.1.0^(2,8)]dec-4-yl,3-azabicyclo[3.2.1]oct-3-yl, 3,7-diazabicyclo3.3.1]non-3-yl,3-azabicyclo[3.3.1]non-3-yl, 8-azabicyclo[3.2.1]oct-8-yl,3-azabicyclo[3.2.2]non-3-yl and tetrahydro-1H-1-benz[6,7-b]azepin-1-yl.

The radicals mentioned may be unsubstituted or N-substituted and/orC-substituted, in which case in particular 1, 2 or 3 substituents may bepresent.

Examples of useful nitrogen substituents are, for example, lower alkyl,lower alkanoyl, (lower alkoxy)carbonyl, (lower alkane)sulphonyl, oxide,aryl or heteroaryl. Carbon substituents are, for example, lower alkyl,hydroxy(lower alkyl), (lower alkoxy)(lower alkyl), (loweralkenyl)oxy(lower alkyl), naphthoxy(lower alkyl), phenyloxy(loweralkyl), phenyl(lower alkoxy)(lower alkyl), (lower alkanoyl)oxy(loweralkyl), benzoyloxy(lower alkyl), (lower alkoxy)carbonyloxy(lower alkyl),phenyloxycarbonyloxy(lower alkyl), phenyl(lower alkoxy)carbonyloxy(loweralkyl), amino(lower alkyl), N-(lower alkyl)amino(lower alkyl),N,N-di(lower alkyl)amino(lower alkyl), carbamoyl(lower alkyl), (loweralkanoyl)amino(lower alkyl), benzoylamino(lower alkyl), (loweralkoxy)carbonylamino(lower alkyl), (lower alkoxy-carbonyl(lower alkyl),(lower alkoxy)(lower alkoxy)(lower alkyl), (lower alkyl)thio(loweralkoxy)(lower alkyl), N-(lower alkoxy)imino(lower alkyl),cycloalkoxy(lower alkyl), cycloalkyl(lower alkoxy)(lower alkyl), loweralkenyl, (lower alkenyl)oxy, (lower alkoxy)(lower alkenyl), loweralkynyl, (lower alkynyl)oxy, lower alkanoyl, oxo, hydroxy, lower alkoxy,carbamoyl(lower alkoxy), N-(lower alkyl)carbamoyl(lower alkoxy),N-(lower alkyl) carbamoyloxy, N,N-di(lower alkyl)carbamoyloxy, (loweralkoxy)(lower alkoxy), (lower alkyl)thio(lower alkoxy), (loweralkanoyl)oxy, benzoyloxy, N-(lower alkyl)carbamoyl, amino, N-(loweralkyl)amino, N,N-di(lower alkyl)amino, (lower alkanoyl)amino,benzoylamino, cycloalkylcarbonylamino, cycloalkyl(lower alkanoyl)amino,(lower alkoxy)carbonyl(lower alkyl)amino, (loweralkenyl)oxycarbonylamino, (lower alkoxy)(lower alkoxy)carbonylamino,(lower alkoxy)(lower alkanoyl)amino, N-(lower alkyl)carbamoylamino,N,N-di(lower alkyl)-carbamoylamino, N-(lower alkanoyl)-N-(loweralkyl)amino, (lower alkoxy)carbonylamino, N-loweralkoxy)carbonyl-N-(lower alkyl)amino, N,N-(lower alkylene)amino,N,N-(1-oxo(lower alkylene))amino, N,N-(1-oxo-2-oxa(loweralkylene))amino, carboxy, (lower alkoxy)carbonyl, phenyl(loweralkoxy)carbonyl, phenyloxycarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl,thiomorpholinyicarbonyl, S,S-dioxothiomorpholin-4-ylcarbonyl, cyano,carbamoyl, N,N-di(lower alkyl)carbamoyl, N-(lower alkenyl)carbamoyl,N-cycloakylcarbamoyl, N-cycloalky(lower alkyl)carbamoyl, N-hydroxy(loweralkyl)carbamoyl, N-(lower alkoxy)(lower alkyl)carbamoyl, N-carboxy(loweralkyl)carbamoyl, carbamoyl(lower alkyl)carbamoyl, (loweralkoxy)carbonyl(lower alkyl)carbamoyl, phenyl, dioxolan-2-yl,oxazol-2-yl, oxazolin-2-yl, oxazolidin-2-yl, nitro, sulphamoyl, (loweralkane)sulphonyl, phosphono, (lower alkane)phosphono, di(loweralkyl)phosphono, polyhalo(lower alkyl) and halogen.

The compound groups mentioned below are not to be regarded as dosed, butrather it is possible in a sensible manner to exchange parts of thesecompound groups with one another or with the definitons given above, orto omit parts, for example to replace general by more specificdefinitions.

Preference is given to compounds of the formula (I) where R₆ is oxygen.

Particularly preferred R radicals are bicydic radicals of the formula(Ia)

where A is a direct bond, methylene, dimethylene, imino, oxy or thio, R₇is (lower alkoxy)(lower alkyl), (lower alkenyl)oxy(lower alkyl), (loweralkoxy)(lower alkoxy)(lower alkyl), (lower alkoxy)carbonylamino(loweralkyl), N-(lower alkoxy)imino(lower alkyl), phenyl, (loweralkoxy)carbonyl, cyano, carbamoyl, N-(lower alkyl)carbamoyl, N-((loweralkoxy)(lower alkyl))carbamoyl, (lower alkoxy), (lower alkoxy)(loweralkoxy), (lower alkanoyl)oxy, benzoyloxy, (lower alkanoyl)amino, (loweralkoxy)carbonylamino, 3- to 6-membered cycloalkylcarbonylamino,N-((lower alkoxy)(lower alkanoyl))amino, N-((loweralkyl)-carbamoyl)amino, N,N-(1-oxo(lower alkylene))amino, orN,N-(1-oxo-2-oxa(lower alkylpene))amino, R₈ is hydrogen or lower alkyland R₉ is hydrogen or halogen.

Above and below, “lower” radicals and compounds refer, for example, tothose which have up to and including 8, preferably up to and including4, carbon atoms.

C₁-C₈-alkylenedioxy is, for example, methylenedioxy or ethylenedioxy,but may also be 1,3- or 1,2-propylenedioxy.

Aryl-C₁-C₈-alkanoyl is one of the aryl radicals mentioned which isbonded to the rest of the compound via a C₁-C₈-alkanoyl group, forexample phenylformyl, phenylacetyl, 3-phenylpropionyl,2-phenyl-2-methylpropionyl or phenylpivaloyl.

Aryl-C₃-C₈-cycloakanoyl is one of the aryl radicals mentioned which isbonded to the rest of the compound via a C₃-C₈-cycloakanoyl group, forexample 1-phenycyclobutanoyl.

Aryl(lower alkyl) is, for example, phenyl- or naphthyl(lower alkyl)which are each unsubstituted or substituted in the phenyl or naphthylmoiety as specified above.

Aryl-C₀-C₈-alkylsulphonyl is one of the aryl radicals mentioned which isbonded to the rest of the compound either via a sulphonyl group or via aC₁-C₈-alklsulphonyl group, for example phenylsulphonyl, benzylsulphonylor phenyldimethylenesulphonyl.

Optionally esterified carboxyl is, for example, carboxyl esterified withC₀-C₆-alkyl, such as carboxyl or C₁-C₆-alkoxycarbonyl.

Cycloalkoxy(lower alkyl) is, for example, C₃-C₈-cycloalkoxy-C₁-C₄-alkyl,such as cyclopropyloxy-C₁-C₄-alkyl, cyclopentyloxy-C₁-C₄-alkyl orcyclohexyloxy-C₁-C₄-alkyl, in particular cyclopropyloxymethyl.

Cycloalkoxy is, for example, C₃-C₈-cycloakoxy, such as cyclopropyloxy,cyclopentyloxy or cyclohexyloxy, in particular cyclopropyloxy.

Cycloalkyl is, for example, 3- to 12-, in particular 3-to 6-memberedcycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl oradamantyl.

Cycloalkylidene is, for example, 3 to 8-, in particular 3- to 6-memberedcycloalkylidene, such as cyclopropylidene, cyclobutylidene,cyclopentylidene or cyclohexylidene.

Cycloalkyl(lower alkyl) is, for example, 3- to 8-, in particular 3- to6-membered cycloalkyl(lower alkyl), such as cyclopropyl-, cyclobutyl-,cyclopentyl- or cyclohexyl(lower alkyl).

N-aryl-N-(lower alkoxy)(lower alkyl)amino is, for example, N-phenyl- orN-naphthyl-N-(lower alkoxy)(lower alkyl)amino which are eachunsubstituted or substituted in the phenyl or naphthyl moiety asspecified above.

N-aryl-N-aryl(lower alkyl)amino is, for example, N-phenyl- orN-naphthyl-N-(phenyl(lower alkyl))amino which are each unsubstituted orsubstituted in the phenyl or naphthyl moiety as specified above.

Cycloalkyl(lower alkanoyl) is, for exampleC₃-C₈-cycloalkyl-C₁-C₄-alkanoyl, such as cyclo-propyl-C₁-C₄-alkanoyl,cyclopentyl-C₁-C₄-alkanoyl or cyclohexyl-C₁-C₄-alkanoyl, in particularcyclopropylacetyl.

C₃-C₈-cycloalkylsulphonyl is, for example, cyclopentylsulphonyl,cyclohexylsulphonyl or cycloheptylsulphonyl, and alsocyclopropylsulphonyl, cyclobutylsulphonyl or cyclooctylsulphonyl.

Halogen is, for example, fluorine, chlorine, bromine or iodine,preferably fluorine and chlorine.

Heterocyclyl-C₀-C₄-alkyl is one of the heterocyclyl radicals mentionedwhich is bonded to the rest of the compound either directly or via aC₁-C₄-alkyl group.

Heterocyclylsulphonyl is one of the heterocyclyl radicals mentionedwhich is bonded to the rest of the compound via a sulphonyl group.

Lower alkanoyl is, for example, C₁-C₈-alkanoyl, in particularC₁-C₄-alkanoyl, such as formyl, acetyl, propionyl, butyryl or pivaloyl.Lower alkanoyl R₃ is in particular formyl, acetyl, propionyl, butyryl,isobutyryl or pivaloyl.

(Lower alkanoyl)amino is, for example, C₁-C₈-alkanoylamino, inparticular C₁-C₄-alkanoylamino, such as acetylamino, propionylamino,butyrylamino or pivaloylamino.

(Lower alkanoyl)amino(lower alkyl) is, for example,C₁-C₈-alkanoylamino-C₁-C₄-alkyl, in particularC₁-C₄-alkanoylamino-C₁-C₄-alkyl, such as formylaminomethyl,acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl,pivaloylaminomethyl, 2-formylaminoethyl, 2-acetylaminoethyl,2-propionylaminomethyl, 2-butyrylaminoethyl or 2-pivaloylaminoethyl.

N-(lower alkanoyl)-N-(lower alkyl)amino is, for example,N-(C₁-C₈-alkanoyl)-N-(C₁-C₄-alkyl)amino, in particularN-(C₁-C₄-alkanoyl)-N-(C₁-C₄-alkyl)amino, such as N-formyl-N-methylamino,N-acetyl-N-methylamino, N-propionyl-N-methylamino orN-butyryl-N-methyl-amino.

(Lower alky)sulphonyl is, for example, C₁-C₈-alkylsulphonyl, inparticular C₁-C₄-alkyl-sulphonyl, such as methylsulphonyl,ethylsulphonyl, propylsulphonyl, prop-2-ylsulphonyl, butylsulphonyl,2-methylpropylsulphonyl, but-2-ylsulphonyl or2,2-dimethylethylsulphanyl.

Lower alkenyl is, for example, C₂-C₈-alkenyl, in particularC₃-C₅-alkenyl, such as allyl.

Lower alkynyl is, for example, C₃-C₈-alkynyl, in particularC₃-C₅-alkynyl, such as propargyl.

Lower alkoxy is, for example, C₁-C₈-alkoxy, in particular C₁-C₄-alkoxy,such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,sec-butyloxy or tert-butyloxy, but may also be a C₅-C₈-alkoxy group,such as a pentyloxy, hexyloxy or heptyloxy group.

(Lower alkoxy)carbonyl is, for example, C₁-C₈-alkoxycarbonyl, inparticular C₁-C₄-alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, propyloxycarbonyl, isopropyl-oxycarbonyl,butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl ortert-butyloxy-carbonyl.

(Lower alkoxy)carbonylamino is, for example, C₁-C₈-alkoxycarbonylamino,in particular C₁-C₄-alkoxycarbonylamino, such as methoxycarbonylamino,ethoxycarbonylamino, propyl-oxycarbonylamino, isopropyloxycarbonylaminoor butyloxycarbonylamino.

(Lower alkoxy)(lower alkanoyl)amino is, for example,C₁-C₄-alkoxy-C₁-C₄-alkanoylamino, such as methoxy-C₁-C₄-alkanoylamino,ethoxy-C₁-C₄-alkanoylamino, propyloxy-C₁-C₄-alkanoylamino,isopropyloxy-C₁-C₄-alkanoylamino or butyloxy-C₁-C₄alkanoylamino, whereC₁-C₄-alkanoyl is, for example, acetyl, propionyl or butyryl.

(Lower alkoxy)(lower alkoxy) is, for example, C₁-C₈-alkoxy-C₁-C₄-alkoxy,in particular C₁-C₄-alkoxy-C₁-C₄-alkoxy, such as methoxy-C₁-C₄-alkoxy,ethoxy-C₁-C₄-alkoxy, propyloxy-C₁-C₄-alkoxy, isopropyloxyl-C₁-C₄-alkoxy,butyloxy-C₁-C₄-alkoxy, isobutyloxy-C₁-C₄-alkoxy,sec-butyloxy-C₁-C₄-alkoxy or tert-butyloxy-C₁-C₄-alkoxy, whereC₁-C₄-alkoxy is, for example, methoxy, ethoxy, propyloxy or butyloxy, inparticular methoxy- or ethoxymethoxy or 2-(methoxy)- or2-(ethoxy)ethoxy.

(Lower alkoxy)(lower alkoxy)(lower alkyl) is, for example,C₁-C₈-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, in particularC₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such asmethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, ethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl,propyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl,isopropyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl orbutyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, where C₁-C₄-alkoxy is, for example,methoxy, ethoxy, propyloxy or butyloxy and C₁-C₄-alkyl is, for example,methyl, ethyl, propyl or butyl, in particular 2-methoxyethoxymethyl.

(Lower alkoxy)(lower alkyl) is, for example, C₁-C₈-alkoxy-C₁-C₄-alkyl,In particular C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy-C₁-C₄-alkyl,ethoxy-C₁-C₄-alkyl, pmpyloxy-C₁-C₄-alkyl, isopropyloxy-C₁-C₄-alkyl,butyloxy-C₁-C₄-alkyl, -isobutyloxy-C₁-C₄-alkyl, sec-butyloxy-C₁-C₄-alkylor tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkyl is, for example, methyl,ethyl, propyl or butyl, in particular ethoxymethyl.

Lower alkyl is branched or unbranched and is, for example, C₁-C₈-alkyl,in particular C₁-C₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl.

N-(lower alkyl)amino is, for example, N—C₁-C₈-alkylamino, in particularC₁-C₄-alkylamino, such as methylamino, ethylamino, propylamino,butylamino, isobutylamino, sec-butylamino or tert-butylamino.

N,N-di(lower alkyl)amino is, for example, N,N-di-C₁-C₄-alkylamino, suchas N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino,N-methyl-N-ethylamino or N-methyl-N-propylamino.

Optionally N-mono or N,N-di-C₁-C₈-alkylated carbamoyl-C₁-C₈-alkyl is,for example, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N-butylcarbamoyl, N-methylcarbamoyl-C₁-C₈-alkyl,N-ethylcarbamoyl-C₁-C₈-alkyl, N-propylcarbamoyl-C₁-C₈-alkyl,N-butylcarbamoyl-C₁-C₈-alkyl , N,N-di-C₁-C₄-alkylamino, such asN,N-dimethyl-carbamoyl-C₁-C₈-alkyl, N,N-diethylcarbamoyl-C₁-C₈-alkyl,N,N-dipropylcarbamoyl-C₁-C₈-alkyl, N-methyl-N-ethylcarbamoyl-C₁-C₈-alkylor N-methyl-N-propylcarbamoyl-C₁-C₈-alkyl, where C₁-C₈-alkyl is, forexample, methyl or ethyl.

N-phenyl-N-(lower alkoxy)(lower alky)amino is, for example,N-phenyl-N—(C₁-C₄-alkoxy-C₁-C₄-alkyl)amino, such asN-phenyl-N-(methoxy-C₁-C₄-alkyl)amino,N-phenyl-N-(ethoxy-C₁-C₄-alkyl)amino,N-phenyl-N-(propyloxy-C₁-C₄-alkyl)amino,N-phenyl-N-(isopropyloxy-C₁-C₄-alkyl)amino orN-phenyl-N-(butyloxy-C₁-C₄-alkyl)amino, where C₁-C₄-alkyl is, forexample, methyl, ethyl, propyl or butyl, in particularN-phenyl-N-(ethoxymethyl)amino.

N-phenyl-N-(lower alkyl)amino is, for example,N-phenyl-N—C₁-C₄-alkylamino, such as N-phenyl-N-methylamino,N-phenyl-N-ethylamino, N-phenyl-N-propylamino, N-phenyl-N-isopropylaminoor N-phenyl-N-butylamino, in particular N-phenyl-N-methylamino.

N-phenyl-N-(phenyl(lower alkyl))amino is, for example,N-phenyl-N-(phenyl-C₁-C₄-alkyl)amino, such as N-phenyl-N-benzylamino,N-phenyl-N-(2-phenylethyl)amino, N-phenyl-N-(3-phenylpropyl)amino orN-phenyl-N-(4-phenylbutyl)amino, in particularN-phenyl-N-(2-phenylethyl)amino.

Phenyl(lower alkanoyl) is, for example, phenyl-C₁-C₄-alkanoyl, whereC₁-C₄-alkanoyl is, for example, acetyl, in particular phenylacetyl.

Polyhalo(lower alkyl) is, for example, di-, tri- ortetrahalo-C₁-C₄-alkyl, such as trifluoromethyl.

Pyridyl(lower alkyl) is, for example pyridyl-C₁-C₄-alkyl, in particularpyrid-2-yl-C₁-C₄-alkyl, where C₁-C₄-alkyl is, for example, methyl, inparticular pyrid-2-ylmethyl or 2-(pyrid-2-yl)ethyl.

Salts of compounds having salt-forming groups are in particular addaddition salts, salts with bases or, in the presence of a plurality ofsalt-forming groups, in some cases also mixed salts or internal salts.Salts are primarily the pharmaceutically usable or nontoxic salts ofcompounds of the formula I.

Such salts are formed, for example, from compounds of the formula I withan acidic group, for example a carboxyl or sulpho group, and are, forexample, the salts thereof with suitable bases, such as nontoxic metalsalts derived from metals of group Ia, Ib, IIa and IIb of the PeriodicTable of the Elements, for example alkali metal, in particular lithium,sodium or potassium salts, alkaline earth metal salts, for examplemagnesium or calcium salts, and also zinc salts or ammonium salts,including those salts which are formed with organic amines, such asoptionally hydroxy-substituted mono-, di- or trialkylamines, Inparticular mono-, di- or tri(lower alkyl)amines, or with quatemaryammonium bases, for example methyl-, ethyl-, diethyl- or triethylamine,mono-, bis- or tris(2-hydroxy(lower alkyl))amines, such as ethanol-,diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or2-hydroxy-tert-butylamine, N,N-di(lower alkyl)-N-(hydroxy(loweralkyl))amines, such as N,N-dimethyl-N-2-hydroxy-ethyl)amine, orN-methyl-D-glucamine, or quaternary ammonium hydroxides, such astetra-butylammonium hydroxide. The compounds of the formula I having abasic group, for example an amino group, may form acid addition salts,for example with suitable inorganic acids, e.g. hydrohalic acid such ashydrochloric acid, hydrobromic add, sulphuric acid with replacement ofone or both protons, phosphoric acid with replacement of one or moreprotons, e.g. orthophosphoric acid or metaphosphoric acid, orpyrophosphoric acid with replacement of one or more protons, or withorganic carboxylic, sulphonic, sulpho or phosphonic acids orN-substituted sulphamic acids, e.g. acetic acid, propionic acid,glycolic acid, succinic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconicacid, glucaric acid, glucuronic acid, ditric acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid, isonicotinic acid, and aIso amino acids, for example the α-aminoacids mentioned above, and also methanesulphonic acid, ethanesulphonicacid, 2-hydroxyethanesulphonic acid, ethane-1,2-disulphonic acid,benzenesulphonic acid, 4-methylbenzenesulphonic acid,naphthalene-2-sulphonic acid, 2- or 3-phosphoglycerate, glucose6-phosphate, N-cyclohexylsulphamic acid (with formation of cyclamates)or with other acidic organic compounds such as ascorbic acid. Compoundsof the formula I with acidic and basic groups may also form internalsalts.

For the isolation and purification, pharmaceutically unsuitable saltsmay also find use.

The invention relates, for example, to compounds of the formula I where

R₁ a) is hydrogen; or

is b) C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, aryl-C₀-C₄-alkyl or heterocyclyl-C₀-C₄-alkyl,which radicals may be substituted by 1-4C₈-alkyl, halogen, cyano, oxide,oxo, trifluoromethyl, C₁-C₈-alkoxy, C₁-C₈-alkoxycarbonyl, aryl orheterocyclyl;

R₂ is a) C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkylsulphonyl,C₃-C₈-cycloalkylsulphonyl, aryl-C₀-C₈-alkylsulphonyl,heterocyclylsulphonyl, C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl,aryl-C₁-C₈-alkanoyl, aryl-C₃-C₈-cycloakanoyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, optionally N-mono- or N,N-di-C₁-C₈-alkylatedcarbamoyl-C₀-C₈alkyl, aryl-C₀-C₄-alkyl or heterocyclyl-C₀-C₄-alkyl,which radicals may be substituted by 1-4 C₁-C₈-alkyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloakoxy, amino, C₁₋₆-alkylamino, di-C₁₋₈-alkylamino,C₀-C₆-alkylcarbonylamino, C₁-C₆-alkoxycarbonylamino, halogen, oxo,cyano, hydroxyl, oxide, trifluoromethyl, C₁-C₈-alkoxy, optionallyN-mono- or N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, optionallyesterified carboxyl, C₁₋₆-alkylenedioxy, aryl or heterocyclyl; or

is b) together with R₁ and the nitrogen atom to which they are bonded, asaturated or partly unsaturated 4-8-membered heterocyclic ring which maycontain an additional nitrogen, oxygen or sulphur atom or a —SO— or—SO2-group, In which case the additional nitrogen atom may optionally besubstituted by C₁-C₈-alkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, arylor heteroaryl radicals, and this heterocyclic ring may be part of abicyclic or tricyclic ring system having a total of up to 16 members andthe second ring may also contain a nitrogen, oxygen or sulphur atom or a—SO— or —SO2-group, and the nitrogen atom in the second ring mayoptionally be substituted by C₁-C₈-alkyl, C₁-C₈-alkanoyl,C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl radicals, and all ringsystems mentioned may be substituted by 1-4C₁-C₈-alkyl, halogen,hydroxyl, cyano, oxide, oxo, trifluoromethyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₁-C₈-alkoxycarbonylamino,C₀-C₈-alkylcarbonylamino, C₁-C₈-alkylamino, N,N-di-C₁-C₈-alkylamino,aryl-C₀-C₄-alkyl, aryloxy-C₀-C₄-alkyl, aryl-C₀-C₄-alkyl-C₁-C₈-alkoxy,aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy, heterocyclyl-C₀-C₄-alkyl,heterocyclyloxy-C₀-C₄-alkyl, heterocyclyl-C₀-C₄-alkyl-C₁-C₈-alkoxy orheterocyclyloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy;

R₃ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl;

R₄ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl;

R₅ are each independently hydrogen or C₁-C₈-alkyl,

R₆ is oxygen,

R is arylamino, N-aryl-N-(lower alkoxy)(lower alkyl))amino,N-aryl-N-aryl(lower alkyl)amino or heterocyclyl bonded via a ringnitrogen atom, in which case the heterocyclyl mentioned, apart from thering nitrogen atom via which it is bonded, may contain further ringheteroatoms selected from oxygen, nitrogen, nitrogen substituted bylower alkyl, lower alkanoyl, (lower alkane)sulphonyl or (loweralkoxy)carbonyl, sulphur, and sulphur bonded to 1 or 2 oxygen atoms,

and salts thereof

The invention relates primarily to compounds of the formula I where R isunsubstituted or anilino or naphthylamino which are each unsubstitutedor substituted in the phenyl or naphthyl moiety as specified below,N-phenyl- or N-naphthyl-N(lower alkoxy)(lower alkyl)amino which are eachunsubstituted or substituted in the phenyl or naphthyl moiety asspecified, N-phenyl- or N-naphthyl-N-(lower alkyl)amino which are eachunsubstituted or substituted in the phenyl or naphthyl moiety asspecified, or 5- to 8-membered heteroacyclyl which is bonded via a ringnitrogen atom and is optionally fused with 1 or 2 fused-on phenyl orcycloalkyl radicals, and which may contain 1 or 2 further ringheteroatoms selected from oxygen, nitrogen and optionally oxidizedsulphur, where phenyl, naphthyl and phenyl or naphthyl radicals as aconstituent of napthylamino, N-phenyl- or N-naphthyl-N-(loweralkoxy)(lower alkyl)amino, N-phenyl- or N-naphthyl-N-(lower alkyl)amino,may be mono- or polysubstituted, for example mono- or disubstituted, bylower alkyl, hydroxy, lower alkoxy, carbamoyl(lower alkoxy), N-(loweralkyl)carbamoyl(lower alkoxy), N-(lower alkyl)carbamoyl, N,N-di(loweralkyl)carbamoyl(lower alkoxy), amino, N-(lower alkyl)- or N,N-di(loweralkyl)amino, carboxy, (lower alkoxy)carbonyl, carbamoyl, sulphamoyl,(lower alkane)sulphonyl, halogen, nitro, phenyl, 5- or 6-memberedheteroaryl containing as a heteroatom 1 nitrogen, sulphur or oxygenatom, 2 nitrogen atoms, 1 nitrogen atom and 1 sulphur atom, or 1nitrogen and 1 oxygen atom, such as pyridyl, and/or by cyano, and Rradicals may be N-substituted by lower alkyl, lower alkanoyl, (loweralkoxy)carbonyl, or (lower alkane)sulphonyl, S-mono- orS,S-disubstituted by oxy, and/or mono- or di-C-substituted by loweralkyl, hydroxy(lower alkyl), (lower alkoxy)(lower alkyl), (loweralkenyl)oxy(lower alkyl), naphthoxy(lower alkyl), phenyloxy(loweralkyl), phenyl(lower alkoxy) (lower alkyl), (lower alkanoyl)oxy(loweralkyl), benzoyloxy(lower alkyl), (lower alkoxy)carbonyloxy(lower alkyl),phenyloxycarbonyloxy(lower alkyl), phenyl(lower alkoxy)carbonyloxy(loweralkyl), amino(lower alkyl), N-(lower alkyl)amino(lower alkyl),N,N-di(lower alkyl)amino(lower alkyl), carbamoyl(lower alkyl), (loweralkanoyl)amino(lower alkyl), benzoylamino(lower alkyl), (loweralkoxy)carbonylamino(lower alkyl), (lower alkoxy)carbonyl(lower alkyl),(lower alkoxy)(lower alkoxy)(lower alkyl), (lower alkyl)thio(loweralkoxy)(lower alkyl), N-(lower alkoxy)imino(lower alkyl),cycloalkoxy(lower alkyl), cycloalkyl(lower alkoxy)(lower alkyl), loweralkenyl, (lower alkenyl)oxy, (lower alkoxy)(lower alkenyl),lower-alkynyl, (lower alkynyl)oxy, lower alkanoyl, oxo, hydroxyl, loweralkoxy, carbamoyl(lower alkoxy), N-(lower alkyl)carbamoyl(lower alkoxy),N-(lower alkyl)carbamoyloxy, N,N-di(lower alkyl)carbamoyloxy, (loweralkoxy)(lower alkoxy), (lower alkyl)thio(lower alkoxy), (loweralkanoyl)pxy, benzoyloxy, N-(lower alkylcarbamoyl, amino, N-(loweralkyl)amino, N,N-di(lower alkyl)amino, (lower alkanoyl)amino,benzoylamino, cycloalkylcarbonylamino, cycloalkyl(lower alkanoyl)amino,(lower alkoxy)carbonyl(lower alkyl)amino, (loweralkenyl)oxycarbonylamino, (lower alkoxy)(lower alkoxy)carbonylamino,(lower alkoxy)(lower alkanoyl)amino, N-(lower alkyl)carbamoylamino,N,N-di(lower alkyl)carbamoylamino, N-(lower alkanoyl)N-(loweralkyl)amino, (lower alkoxy)carbonylamino, N-(loweralkoxy)carbonyl-N-(lower alkyl)amino, N,N-(lower alkylene)amino,N,N-(1-oxo(lower alkylene))amino, N,N(1-oxo-2-oxa(lower alkylene))amino,carboxyl, (lower alkoxy)carbonyl, phenyl(lower alkoxy)carbonyl,phenyloxycarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl,S,S-dioxothiomorpholinylcarbonyl, cyano, carbamoyl, N,N-di(loweralkyl)carbamoyl, N-(lower alkenyl)carbamoyl, N-cycloalkylcarbamoyl,N-cycloalkyl(lower alkyl)carbamoyl, N-hydroxy(lower alkyl)carbamoyl,N-(lower alkoxy)(lower alkyl)carbamoyl, N-carboxy(lower alkyl)carbamoyl,carbamoyl(lower alkyl)carbamoyl, (lower alkoxy)carbonyl(loweralkyl)carbamoyl, phenyl, dioxolan-2-yl, oxazol-2-yl, oxazolin-2-yl,oxazolidin-2-yl, nitro, sulphamoyl, (lower alkane)sulphonyl, phosphono,(lower alkane)phosphono, di(lower alkyl)phosphono and/or halogen.

The inventon relates in particular to compounds of the formula I where Ris an anilino, naphthylamino, N-phenyl-N-(C₁-C₄-alkoxy-C₁-C₄-alkyl)aminosuch as N-phenyl-N-(ethoxymethyl)amino, orN-phenyl-N-(phenyl-C₁-C₄-alkyl)amino such asN-phenyl-N-(2-phenylethyl)amino which are each unsubstituted, or mono-or disubstituted in the phenyl or naphthyl moiety by C₁-C₄-alkoxy suchas methoxy, C₁-C₄-alkoxycarbonyl such as methoxy-, ethoxy-,isopropyloxy- or tert-butyloxycarbonyl, carbarmoyl-C₁-C₄-alkoxy such ascarbamoylmethoxy, C₁-C₄-alkanoylamino-C₁-C₄-alkyl such asformylaminomethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkyl such asmethoxycarbonylaminomethyl, halogen and/or optionally N-oxidized pyridylsuch as pyrid-3-yl or 1-oxidopyrid-3-yl, or is pyrrolidino, piperidino,piperazine, morpholino or thiomorpholino, indolin-1-yl, isoindolin-2-yl,2,3-dihydrobenzimidazol-1-yl, 1,2,3,4-tetrahydroquinol-1-yl,1,2,3,4-tetrahydroisoquinol-2-yl,1,2,3,4-tetrahydro-1,3benzodiazin-1-yl,1,2,3,4-tetrahydro-1,4-benzodiazin-1-yl,3,4-dihydro-2H-1,4-benzoxazin-4-yl, optionally S,S-dioxidized3,4-dihydro-2H- ,3-benzothiazin-1-yl,3,4,5,6,7,8-hexahydro-2H-1,4-benzoxazin-4-yl,3,4,5,6,7,8-hexahydro-2H-1,4-benzothlazin-4-yl,2,3,4,5-tetrahydro-1H-1-benzo[6,7-b]azepin-1-yl or5,6-dihydrophenanthridin-5-yl which are each unsubstituted or mono-, di-or trisubstituted by C₁-C₄-alkyl such as methyl, hydroxy-C₁-C₄-alkylsuch as hydroxymethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl such as methoxymethyl orpropyloxymethyl, C₃-C₅-alkenyloxy-C₁-C₄-alkyl such as allyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl such as methoxymethoxymethyl or2-methoxyethoxymethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkyl such asmethoxy- or ethoxycarbonylaminomethyl, C₁-C₄-alkoxyimino-C₁-C₄-alkylsuch as methoxyiminomethyl, ethoxylminomethyl or propoxyiminomethyl,carboxyl, C₁-C₄-alkoxycarbonyl such as methoxy-, ethoxy-, isopropyloxy-or tert-butyloxycarbonyl, cyano, carbamoyl, N—C₁-C₈-alkylcarbamoyl suchas N-methyl- or N-butylcarbamoyl, N,N-di-C₁-C₄alkylcarbamoyl such asN,N-dimethyl-carbamoyl, C₁-C₄-alkoxy-C₁-C₄-alkylcarbamoyl such asN-(2-propyloxyethyl)carbamoyl, N-carboxy-C₁-C₄-alkylcarbamoyl such asN-carboxymethylcarbamoyl, morpholinocarbonyl, C₁-C₄-alkoxy such aspropyloxy, C₁-C₄-alkoxy-C₁-C₄-alkoxy such as methoxymethoxy or2-methoxyethoxy, C₁-C₄-alkanoyloxy such as acetoxy or benzoyloxy,C₁-C₄-alkanoylamino, such as acetylamino, C₁-C₄-alkoxycarbonylamino suchas methoxycarbonylamino, 3- to 6-membered cycloakylcarbonylamino such ascyclopropylcarbonylamino, N—C₁-C₄-alkoxy-C₁-C₄alkanoylamino such asmethoxyacetylamino, N—C₁-C₄-alkylcarbamoylamino such asmethylcarbamoylamino, or 5- or 6membered N,N-(1-oxo(loweralkylene))amino or N,N(1-oxo-2-oxa(lower-alkylene))amino such as2-oxopyrrlidin-1-yl or 2-oxooxazolidin-3-yl, C₁-C₈-alkanoyl such asacetyl, oxo, nitro, C₁-C₄-alkanesulphonyl such as methane- orethanesulphonyl, and/or halogen.

The invention relates in particular to compounds of the formula I whereR is a group of the formula

in which

A is a direct bond, methylene, dimethylene, imino, oxy or thio,

R₇ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy- or propyloxymethyl,C₃-C₅-alkenyloxy-C₁-C₄-alkyl, such as allyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxymethoxymethyl or2-methoxyethoxymethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkyl, such asmethoxy- or ethoxycarbonylaminomethyl, C₁-C₄-alkoxyimino-C₁-C₄-alkyl,such as methoxyiminomethyl, phenyl, C₁-C₄-alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl or isopropyloxycarbonyl, cyano,carbamoyl, N—C₁-C₄-alkylcarbamoyl, such as N-methylcarbamoyl,N-ethylcarbamoyl or N-butylcarbamoyl, C₁-C₄-alkoxy-C₁-C₄-alkylcarbamoyl,such as N-(2-methoxyethyl)carbamoyl, C₁-C₄-alkoxy such as propyloxy,C₁-C₄-alkoxy-C₁-C₄-alkoxy such as methoxymethoxy or 2-methoxyethoxy,C₁-C₈-alkanoyloxy such as acetoxy, benzoyloxy,N—C₁-C₄-alkylcarbamoylamino, such as N-methylcarbamoyl-amino,C₁-C₄-alkanoylamino, such as acetylamino, C₁-C₄-alkoxycarbonylamino,such as methoxycarbonylamino, 3 to 6-membered cycloakylcarbonylamino,such as cyclopropylcarbonylamino, C₁-C₄-alkoxy-C₁-C₄-alkanoylamino, suchas methoxyacetylamino, or 5- or 6-membered N,N-(1-oxo(loweralkylene))amino or N,N-1-oxo-2-oxa(lower alkylene))amino, such as2-oxopyrrolidin-1-yl or 2-oxooxazolidin-3-yl,N—C₁-C₄-alkyl-carbamoylamino, such as methylcarbamoylamino,

R₈ is hydrogen, but may also be C₁-C₄-alkyl such as methyl,

R₉ is hydrogen or halogen and

R₁₀ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy-C₁-C₄-alkyl,ethoxy-C₁-C₄-alkyl, propyloxy-C₁-C₄-alkyl, isopropyloxy-C₁-C₄-alkyl,butyloxy-C₁-C₄-alkyl, isobutyloxy-C₁-C₄-alkl, sec-butyloxy-C₁-C₄-alkylor tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkyl is, for example, ethyl,propyl or butyl, and is in particular 3-methoxypropyl.

Particularly effective in each case are those compounds of the formula Iwith the stereochemistry (in each case “S”) of the main chain shown inthe formula

The invention relates in each case preferentially to the stereoisomersof compounds of the formula I with the stereochemistry of the main chainshown in the formula Ic, where the variables are each defined asfollows, and salts thereof, in particular pharmaceutically usable saltsthereof.

The invention relates specifically to the compounds of the formula Ispecified in the examples and to salts thereof, in particular topharmaceutically usable salts thereof.

The invention relates primarily to compounds of the formula

where

A is methylene, oxy or thio,

R₁ is a) hydrogen; or

is b) C₁-C₈-alkyl or C₃-C₈-cycloalkyl;

R₂ is a) C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkanoyl,heterocyclyl-C₁-C₈-alkanoyl, C₃-C₁₂-cycloalkyl-C₁-C₈-alkanoyl oraryl-C₁-C₈-alkanoyl, which radicals may be substituted by 1-4C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkoxy, C₁₋₆alkylamino, cyano,halogen, hydroxyl, oxide, C₀-C₆-alkylcarbonylamino, C₁-C₈-alkoxy, oxo,trifluoromethyl or aryl; or

b) together with R₁ and the nitrogen atom to which they are bonded, is asaturated or partly unsaturated, 4-8-membered heterocyclic ring whichmay contain an additional nitrogen or oxygen atom, in which case theadditional nitrogen atom may optionally be substituted by C₁-C₈-alkyl orC₁-C₈-alkanoyl, and this heterocyclic ring may be part of a bicyclic ortricyclic ring system having a total of up to 16 members, and the secondring may also contain a nitrogen or oxygen atom, in which case thenitrogen atom of the second ring may optionally be substituted byC₁-C₈-alkyl or C₁-C₈-alkanoyl, and all ring systems mentioned may besubstituted by 1-4 C₁-C₈-alkyl, hydroxyl, cyano, oxide, oxo,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₁-C₈-alkylcarbonylamino,C₁-C₈-alkoxycarbonylamino or aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy;

R₃ is hydrogen or —(C═O)—C₁-C₄-alkyl;

R₄ is hydrogen;

R₅ are each independently C₁-C₄-alkyl, such as methyl,

R₇ is C₁-C₄-alkoxycarbonylamino such as methoxycarbonylamino,ethoxycarbonylamino, propyloxycarbonylamino, isopropyloxycarbonylaminoor butyloxycarbonylamino, C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such asmethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, ethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl,propyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, isopropyloxy C₁-C₄-alkoxy-C₁-C₄-akylor butyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, where C₁-C₄-alkoxy is, forexample, methoxy, ethoxy, propyloxy or butyloxy, and C₁-C₄-alkyl is, forexample, methyl, ethyl, propyl or butyl, in particularmethoxymethoxymethyl, 2-methoxyethoxymethyl or 3-methoxypropyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy-C₁-C₄-alkyl,ethoxy-C₁-C₄-alkyl, propyloxy-C₁-C₄-alkyl, isopropyloxy-C₁-C₄-alkyl,butyloxy-C₁-C₄-alkyl, isobutyloxy-C₁-C₄-alkyl, sec-butyloxy-C₁-C₄-alkylor tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkyl is, for example, methyl,ethyl, propyl or butyl, in particular ethoxymethyl or 2-methoxyethyl, orN—C₁-C₄-alkylcarbamoyl, such as N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl or N-butylcarbamoyl, and salts thereof, in particularthe pharmaceutically usable salts thereof.

The compounds of the formula (I) may be prepared in an analogous mannerto preparation processes known from the literature. The startingmaterials for carrying out the preparation processes are described, forexample, in EP 0702004. The inventive compounds of the formula (I) andsalts of such compounds having at least one salt-forming group areobtained by processes known per se, for example by

a) condensing a compound of the formula II

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,with a compound of the formula R₁R₂NH (III) where R₁ and R₂ are each asdefined above, in the course of which free functional groups present inthe reaction components with the exception of the groups taking part inthe reaction are present in protected form, and protecting groupspresent are detached. In cases where R₁ and R₂ are a saturated or partlyunsaturated oxo-substituted heterocyclic ring (for example lactams) andstrong bases are used as a reagent, the alkoxide formed by epoxideopening can react with one of the protecting groups present (for exampleN-Boc) and form an oxazolidinone which can be cleaved to give theproduct, for example, with lithium hydroxide, or

b) condensing a compound of the formula II

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,with an azide, reducing the azido group to amino and then, dependingupon the definitions of R₁ and R₂ mono- or dialkylating, mono- ordiacylating, and optionally sulphonylating the amino group, in thecourse of which free functional groups present in the reactioncomponents with the exception of the groups taking part in the reactionare present in protected form, and detaching protecting groups present,or

c) condensing a compound of the formula IV

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,with cyanide or nitromethane, reducing the nitrile group or nitro groupto amino and then, depending upon the definitions of R₁ and R₂, mono- ordialkylating, mono- or diacylating, and optionally sulphonylating theamino group, in the course of which free functional groups present inthe reaction components with the exception of the groups taking part inthe reaction are present in protected from, and detaching protectinggroups present.

Compounds of the formula II can be prepared in an analogous manner topreparation processes known from the literature, for example by

a) condensing a compound of the formula IV

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,with methylide (see, for example, in Tet. Lett. 30(40), 5425-5428,1989), in the course of which free functional groups present in thereaction components with the exception of the groups taking part in thereaction are present in protected form, and detaching protecting groupspresent, or

b) epoxidizing a compound of the formula V

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,(see, for example, in J. Med. Chem. 35(10), 1685-1701, 1992 and J. Org.Chem. 59(3), 653657, 1994), in the course of which free functionalgroups present in the reaction components with the exception of thegroups taking part in the reaction are present in protected form, anddetaching protecting groups present, or

c) dihydroxylating a compound of the formula V

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,tosylating the primary alcohol and subsequently admixing it with a basesuch as potassium hydroxide (see, for example, in WO 03050073), in thecourse of which free functional groups present in the reactioncomponents with the exception of the groups taking part in the reactionare present in protected form, and detaching protecting groups present,or

d) preparing an activated ester from a compound of the formula VI

where R, R₃, R₄, R₅ and R₆ are each as defined above, or a salt thereof,and admixing it with diazomethane, admixing the diazoketone with 48%HBr, and then reducing the bromoketone, and subsequently admixing itwith a base such as potassium hydroxide (see, for example, in WO03050073), in the course of which free functional groups present In thereaction components with the exception of the groups taking part in thereaction are present in protected form, and detaching protecting groupspresent.

Details of the specific preparation variants can be taken from theexamples.

The compounds of the formula (I) may also be prepared in optically pureform. The separation into antipodes may be effected by methods known perse, either preferably at a synthetically early stage by salt formationwith an optically active acid, for example (+)- or (−)-mandelic acid andseparation of the diastereomeric salts by fractional crystallization, orpreferably at a rather later stage by derivatization with a chiralauxiliary building block, for example (+)- or (−)-camphanoyl chloride,and separation of the diastereomeric products by chromatography and/orcrystallization and subsequent cleavage of the bond to the chiralauxiliary. To determine the absolute configuration of the piperidinepresent, the pure diastereomeric salts and derivatives may be analysedwith common spectroscopic methods, of which X-ray spectroscopy on singlecrystals constitutes a particularly suitable method.

Prodrug derivatives of the compounds described in the present contextare derivatives thereof which, on in vivo application, release theoriginal compound by a chemical or physiological process. A prodrug maybe converted to the original compound, for example, when a physiologicalpH is attained or by enzymatic conversion. Prodrug derivatives may, forexample, be esters of freely available carboxylic acids, S— and O-acylderivatives of thiols, alcohols or phenols, and the acyl group is asdefined in the present context. Preference is given to pharmaceuticallyusable ester derivatives which are converted by solvolysis inphysiological medium to the original carboxylic acid, for example loweralkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters,mono- or disubstituted lower alkyl esters such as lower ω-(amino, mono-or dialkylamino, carboxyl, lower alkoxycarbonyl)-alkyl esters or such aslower α-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)-alkylesters; as such, pivaloyloxymethyl esters and similar esters areutilized in a conventional manner.

Owing to the dose relationship between a free compound, a prodrugderivative and a salt compound, a certain compound in this inventionalso encompasses its prodrug derivative and salt form, where this ispossible and appropriate.

The compounds of the fbrmula (I) also include those compounds in whichone or more atoms are replaced by their stable, non-radioactiveisotopes; for example, a hydrogen atom by deuterium.

The compounds of the formula (I) and the pharmaceutically usable saltsthereof have inhibiting action on the natural enzyme renin. The latterpasses from the kidneys into the blood and there brings about thedeavage of angiotensinogen to form the decapeptide angiotensin I whichis then cleaved in the lung, the kidneys and other organs to theoctapeptide angiotensin II. Angiotensin II increases the blood pressureboth directly by arterial constriction and indirectly by the release ofthe hormone aldosterone which inhibits the release of the sodium ionfrom the adrenal glands, which is associated with a rise in theextracellular liquid volume. This rise can be attributed to the actionof angiotensin II itself or of the heptapeptide angiotensin III formedtherefrom as a cleavage product. Inhibitors of the enzymatic activity ofrenin bring about a reduction in the formation of angiotensin I and, asa consequence thereof, the formation of a smaller amount of angiotensinII. The reduced concentration of this active peptide hormone is theimmediate cause of the hypotensive action of renin inhibitors.

The action of renin inhibitors is detected experimentally with an invitro test [Nussberger et al. (1987) J. Cardiovascular Pharmacol., Vol.9, p. 39-44]. This test measures the formation of angiotensin I in humanplasma. The amount of angiotensin I formed is determined in a subsequentradioimmunoassay. Which action inhibitors have on the formation ofangiotensin I is tested in this system by the addition of differentconcentrations of these substances. The IC₅₀ refers to thatconcentration of the particular inhibitor which reduces the formation ofangiotensin I by 50%. The compounds of the present invention exhibitinhibiting actions in the in vitro systems at minimum concentrations ofabout 10⁻⁶ to about 10⁻¹⁰ mol/I.

In salt-depleted animals, renin inhibitors bring about a blood pressuredecrease. Human renin differs from renin of other species. To testinhibitors of human renin, primates (marmosets, Callithrixjacchus) areused, because human renin and primate renin are substantially homologousin the enzymatically active region. One in vivo test which is used is asfollows: the test compounds are tested on normotensive marmosets of bothgenders and having a body weight of about 350 g which are conscious,able to move freely and in their normal cages. Blood pressure and heartrate are measured using a catheter in the descending aorta and recordedradiometrically. The endogenous release of renin is stimulated by thecombination of a 1-week low-salt diet with a single intra-muscularinjection of furosemide(5-(aminosulphonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5mg/kg). 16 hours after the injection of furosemide, the test substancesare administered either directly into the femoral artery by means of aninjection cannula or into the stomach by gavage as a suspension orsolution, and their effect on blood pressure and heart rate isevaluated. The compounds of the present invention effectively reduceblood pressure in the in vivo test described at doses of about 0.003 toabout 0.3 mg/kg i.v. and at doses of about 0.3 to about 30 mg/kg p.o.

The compounds of the formula (I) and the pharmaceutically usable saltsthereof may find use as medicines, for example in the form ofpharmaceutical preparations. The pharmaceutical preparations may beadministered enterally, such as orally, for example in the form oftablets, coated tablets, sugar-coated tablets, hard and soft gelatinecapsules, solutions, emulsions or suspensions, nasally, for example inthe form of nasal sprays, rectally, for example in the form ofsuppositories, or transdermally, for example in the form of ointments orpatches. The administration may also be parenteral, such asintramuscular or intravenous, for example in the form of injectionsolutions.

To prepare tablets, coated tablets, sugar-coated tablets and hardgelatine capsules, the compounds of the formula (I) and pharmaceuticallyusable salts thereof may be processed with pharmaceutically inert,inorganic or organic excipients. Such excipients used, for example fortablets, coated tablets and hard gelatine capsules, may be lactose, cornstarch, or derivatives thereof, talc, stearic acid or salts thereof etc.

Suitable excipients for soft gelatine capsules are, for example,vegetable oils, waxes, fats, semisolid and liquid polyols, etc.

Suitable excipients for preparing solutions and syrups are, for example,water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.

Suitable excipients for suppositories are, for example, natural orhardened oils, waxes, fats, semisolid or liquid polyols, etc.

The pharmaceutical preparations may additionally also comprisepreservatives, solubilizers, viscosity-increasing substances,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavourings, salts for altering the osmotic pressure, buffers, coatingsor antioxidants. They may also comprise other the therapeuticallyvaluable substances.

The present invention further provides the use of the compounds of theformula (I) and the pharmaceutically usable salts thereof in thetreatment or prevention of hypertension and heart failure, and alsoglaucoma, cardiac infarction, kidney failure and restenoses.

The compounds of the formula (I) and the pharmaceutically usable saltsthereof may also be administered in combination with one or more agentshaving cardiovascular action, for example α- and β-blockers such asphentolamine, phenoxybenzamine, prozosin, terazosin, tolazine, atenolol,metoprolol, nadolol, propranolol, timolol, carteolol etc.; vasodilatorssuch as hydralazine, minoxidil, diazoxide, nitroprusside, flosequinanetc.; calcium antagonists such as amrinone, bencyclan, diltiazem,fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil,gallopamil, nifedipine etc.; ACE inhibitors such as cilazapril,captopril, enalapril, lisinopril etc.; potassium activators such aspinacidil; anti-serotoninergics such as ketanserin;thromboxane-synthetase inhibitors; neutral endopeptidase inhibitors (NEPinhibitors); angiotensin II antagonists; and also diuretics such ashydrochlorothiazide, chlorothiazide, acetazolamide, amiloride,bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone,metolazone, spironolactone, triamteren, chlorthalidone etc.;sympatholytics such as methyldopa, donidine, guanabenz, reserpine; andother agents which are suitable for the treatment of hypertension, heartfailure or vascular diseases in humans and animals which are associatedwith diabetes or renal disorders such as acute or chronic renal failure.Such combinations may be employed separately or in preparations whichcomprise a plurality of components.

Further substances which can be used in combination with the compoundsof the formula (I) are the compounds of classes (i) to (ix) on page 1 ofWO 02140007 (and also the preferences and examples further listedtherein) and the substances specified on pages 20 and 21 of WO03/027091.

The dose may vary within wide limits and has of course to be adapted tothe individual circumstances In each individual case. In general, fororal administration, a daily dose of about 3 mg to about 3 g, preferablyabout 10 mg to about 1 g, for example about 300 mg, per adult (70 kg),divided into preferably 1-3 individual doses which may, for example, beof equal size, may be appropriate, although the upper limit specifiedmay also be exceeded if this should be found to be appropriate;typically, children receive a lower dose according to their age and bodyweight.

The examples which follow illustrate the present invention. Alltemperatures are reported in degrees Celsius, pressures in mbar. Unlessstated otherwise, the reactions take place at room temperature. Theabbreviation “Rf=xx (A)” means, for example, that the Rf value xx isobtained In the solvent system A. The ratio of the solvents relative toone another is always reported in parts by volume. Chemical names of endproducts and intermediates were obtained with the aid of the programAutoNom 2000 (Automatic Nomenclature).

HPLC gradients on Hypersil BDS C-18 (5 μm); column: 4×125 mm

-   -   I 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile*        in 5 minutes+2.5 minutes (1.5 ml/min)    -   II 95% water*/15% acetonitrile* to 0% water*/100% acetonitrile*        in 40 minutes (0.8 ml/min)

*: containing 0.1% trifluoroacetic acid

The following abbreviations are used:

Rf ratio of the distance which a substance travels to the distance ofthe eluent front from the starting point in thin layer chromatography

Rt retention time of a substance in HPLC (in minutes)

m.p. melting point (temperature)

General Method A: (N-BOC Deprotection)

A solution of 0.2 mmol of “N-BOC derivative” in 2 ml of 4N HCl (indioxane) is stirred for 2-6 hours at 0° C. The mixture is concentratedand tert-butanol is added to the residue. The title compound is obtainedfrom the residue by lyophilization.

EXAMPLE 1[1-(5(S)-Amino-6(S-hydroxy-3,3-dimethyl-7-piperidin-1-yl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester dihydrochloride

Analogously to Method A, 0.040 g of[1-(5(S)-tert-butoxycarbonylamino-6(S)-hydroxyo-3,3-dimethyl-7-piperidin-1-yl-heptanoyl)1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester are used to prepare the title compound which isobtained as a white solid. Rf=0.18 (200:40:1dichloromethane-methanol-25% conc. ammonia); Rt=2.82 (gradient I).

The starting materials are prepared as follows:

a)[1-(5(S)tert-Butoxycarbonylamino-6(S-hydroxy-3,3-dimethyl-7-piperidin-1-yl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

A solution of 0.030 g of[1-(5(S)-tert-butoxycarbonylamino-3,3-dimethyl-5-(R)-oxiranyl-pentanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester and 0.05 ml piperidine in 0.6 ml of isopropanol isstirred at 70° C. for 1 hour, then cooled to room temperature andconcentrated. The title compound is obtained as a beige oil from theresidue by means of flash chromatography (SiO2 60F). Rt=3.89 (gradientI).

b)[1-(5(S)-tert-Butoxycarbonylamino-3,3-dimethyl-5-(R)-oxiranyl-pentanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

8.69 g of magnesium monoperoxyphthalate hexahydrate are added to asolution of 1.69 g of[1-(5(S)tert-butoxycarbonylamino-3,3-dimethyl-hept-6-enoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)yl]-carbamicacid methyl ester in 30 ml of methanol under argon at room temperatureand the mixture is stirred at room temperature for 4 days. The mixtureis poured into a mixture of ice and saturated aqueous sodium bicarbonatesolution and extracted with tert-butyl methyl ether (2×). The combinedorganic layers are washed with water and brine, dried over sodiumsulphate, filtered and concentrated. The title compound is obtained as awhite solid from the residue by means of flash chromatography (SiO260F). Rf=0.5 (3:2 EtOAc-heptane); Rt=4.34 (gradient I).

c)[1-(5(S)-tert-Butoxycarbonylamino-3,3-dimethyl-hept-6-enoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

4.60 g of methyltriphenylphosphonium bromide are added to a solution of2.70 g of solid potassium bis(trimethylsilyl)amide in 60 ml of diethylether under argon at 0° and the mixture is stirred 30 minutes at 0° C. Asolution of 1.98 g of[1-(5(S)-tert-butoxycarbonylamino-3,3-dimethyl-oxo-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester in 20 ml of diethyl ether is added dropwise at 0° C.The mixture is stirred at 0° C. for 1 hour, then poured into saturatedaqueous ammonium chloride solution and extracted with tert-butyl methylether (2×). The combined organic layers are washed with water and brine,dried over sodium sulphate, filtered and concentrated. The titlecompound is obtained as a white solid from the residue by means of flashchromatography (SiO2 60F). Rf=0.28 (1:1 EtoAc-heptane); Rt=4.79(gradient I).

d)[1-(5(S)-tert-butoxycarbonylamino-3,3-dimethyl-6-oxo-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

2.10 ml of triethylamine are added to a solution of 2,34 g of[1-(5(S)tert-butoxycarbonylamino-6-hydroxy-3,3-dimethyl-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester in 20 ml of methylene chloride under argon at 0° C.The mixture is stirred for 5 minutes at 0° C. and then a solution of2.65 g of pyridine sulfur trioxide in 12 ml of dimethylsulfoxide isadded dropwise at 0-5° C. over 1 hour. The mbdture is stirred at 0-5° C.for 30 minutes and then ice water is added dropwise to the mixture at0-10° C. The mixture is stirred at 10° C. for 10 minutes and thenextracted with methylene chloride (3×). The combined organic layers arewashed successively with 10% aqueous sodium hydrogensulfate solution,water, 10% aqueous sodium bicarbonate solution and brine, dried oversodium sulphate, filtered and concentrated. The title compound isobtained as a white solid. Rf=0.44 (3:1 EtOAc-heptane); Rt=4.17(gradient I).

e)[1-(5(S)tert-Butoxycarbonylamino-6-hydroxy-3,3-dimethyl-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-carbamicacid methyl ester

A solution of 3.1 g of4(S)-[4-(3(R,S)-methoxycarbonylamino-3,4-dihydro-2H-quinolin-1-yl)-2,2-dimethyl-4-oxo-butyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester and 104 mg of p-toluenesulfonic acid monohydratein 49 ml of methylene chloride under argon is stirted at roomtemperature for 3.5 hours. More p-toluenesulfonic acid monohydrate (200mg) is added and the mixture is stirred at room temperature for 1.5hours The solution is concentrated. The title compound is obtained as awhite solid from the residue by means of flash chromatography (SiO260F). Rf=0.14 (3:1 EtOAc-heptane); Rt=3.91 (gradient I).

f)4(S)-[4-(3(R,S)-Methoxycarbonylamino-3,4-dihydro-2H-quinolin-1-yl)-2,2-dimethyl-4-oxo-butyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

8.88 ml of triethylamine are added to a solution of 6.67 g of4(S)-(3-carboxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester in 200 ml of methylene chloride under argon. Themixture is cooled to 15° C. and 5.54 g ofbis(2-oxo-3-oxazolidinyl)phosphinic chloride are added. The mixture isstirred at room temperature for 2 hours. A solution of 4.36 g of(1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester[177202-73-2] in 100 ml of methylene chloride is added, followed byaddition of 2.11 g of 4-N,N-dimethylaminopyridine. The reaction mixtureis stirred at room temperature for 17 hours. The mixture is poured into1M NaOH and extracted with tert-butyl methyl ether (2×). The combinedorganic layers are washed with water and brine, dried over sodiumsulphate, filtered and concentrated. The title compound is obtained as aslightly yellow oil from the residue by means of flash chromatography(SiO2 60F). Rf=0.39 (1:3 EtOAc-heptane); Rt=5.03 (gradient I).

g)4(S)-(3-Carboxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicadd tert-butyl ester

647 mg of lithium hydroxide monohydrate are added to a solution of 1.13g of4(S)-(3-ethoxycarbonyl-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester in 50 ml of tetrahydrofuran, 50 ml of methanol and50 ml of water. The mixture is stirred at room temperature for 16.5hours and concentrated. Water and ethyl acetate are added to themixture. The layers are separated and the aqueous layer is extractedwith ethyl acetate (2×). The aqueous layer is acidified to pH 3 with 4MHCl and extracted with ethyl acetate (3×). The combined organic layersfrom the second extraction are dried over sodium sulphate, filtered andconcentrated. The title compound is obtained as a colourless oil fromthe residue by means of flash chromatography (SiO2 60F). Rf=0.29 (1:1EtOAc-heptane+1% AcOH); Rt=4.31 (gradient I).

h)4(S)-(3-Ethoxycarbonyl-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

2.23 g of silver oxide are added to a solution of 3.58 g of4(S)-(4-diazo-2,2-dimethyl-3-oxo-butyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester in 150 ml of absolute ethanol under argon. Themixture is stirred at 50° C. for 5 hours. The mixture is filtered overHyflo® and concentrated. The title compound is obtained as a colourlessoil from the residue by means of flash chromatography (SiO2 60F).Rf=0.38 (1:3 EtOAc-heptane); Rt=5.49 (gradient I).

i)4(S)-(4-Diazo-2,2-dimethyl-3-oxo-butyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a solution of 5.43 g of(S)-4-(2-carboxy-2-methyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicadd tert-butyl ester in 160 ml of methylene chloride under argon issuccessively added 2.19 ml of pyridine, 0.1 ml of N,N-dimethylformamidand 3.18 ml of oxalyl chloride. The mixture is stirred at roomtemperature for 1.5 hours, and then 550 ml of diazomethane solution(0.02 M in ether) are added dropwise. The mixture is concentrated. Thetitle compound is obtained as a yellow oil from the residue by means offlash chromatography (SiO2 60F). Rf=0.37 (1:3 EtOAc-heptane); Rt=4.65(gradient I).

j)4(S)-(2-Carboxy-2-methyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

A mixture of 9.48 g of4(S)-(2-benzyloxycarbonyl-2-methyl-propyl)-2,2-dimethyl-oxazlidine-3-carboxylicacid tert-butyl ester and 2.58 9 of 10% Pd/C in 100 ml of ethyl acetateis hydrogenated at room temperature for 4.5 hours. The solid is removedby filtration over Hyflo®. The mixture is concentrated and re-dissolvedin ethyl acetate and 2N NaOH. The layers are separated and the aqueouslayer is extracted with ethyl acetate (2×). The aqueous layer isacidified to pH 3 with 4M HCl and extracted with ethyl acetate (3×). Thecombined organic layers from the second extraction are dried over sodiumsulphate, filtered and concentrated. The crude title compound isobtained as a colourless oil. Rf=0.43 (EtOAc-heptane 1:1); Rt=4.23(gradient I).

k)4(S)-(2-Benzyloxycarbonyl-2-methyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a solution of 247.3 ml of lithium bis(trimethylsilyl)amide (1M intetrahydrofuran) in 100 ml of tetahydrofuran at −78° C. is added 15.55ml of methyl iodide. The mixture is stirred at −78° C. for 10 minutes. Asolution of 33.28 g of4(S)-(2-benzyloxycarbonyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester in 100 ml of tetrahydrofuran is added dropwise tothe mixture at −78° C. The mixture is stirred at −78° C. for 15 minutes,and at 0° C. for 45 minutes. Saturated ammonium chloride solution isadded dropwise to the mixture, followed by water. The mixture isextracted with tert-butyl methyl ether (2×). The combined organic layersare dried over sodium sulphate, filtered and concentrated. The titlecompound is obtained as a yellow oil from the residue by means of flashchromatography (S802 60F). Rf=0.24 (1:5 EtOAc-heptane); Rt=5.83(gradient I).

l) 4(S)-(2-Benzyloxycarbonyl-ethyl)-2,2-dimethyl-oxalidine-3-arboxylicacid tert-butyl ester

To a solution of 52.46 g of4(S)-tert-butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester[9069-62-8] and 895 mg of p-toluenesulfonic acid hydrate in 125 ml ofmethylene chloride at 0° C. under argon are added 31 ml ofmethoxypropene over 15 minutes. The mixture is stirred at 0° C. for 3hours, then at room temperature for 9 hours. The mixture is washed withsaturated sodium bicarbonate solution and dried over sodium sulphate,filtered and concentrated. The title compound is obtained as a yellowoil from the residue by means of flash chromatography (SiO2 60F).Rf=0.32 (1:3 EtOAc-heptane); Rt=5.32 (gradient I).

Alternative Method (I) for the Synthesis of Compound 1 g:

To a solution of 870 mg of4(S)-(3-cyano-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester and 597 mg of potassium hydroxide in 6.68 ml ofethylene glycol is added 0.1 ml of water. The mixture is heated to 200°C. for 8 hours. The mixture is cooled to room temperature and thendiluted with water and ethyl acetate. The layers are separated and theaqueous layer is extracted with ethyl acetate (2×). The aqueous layer isacidified to pH 3 with 4M HCl and extracted with ethyl acetate (3×). Thecombined organic layers from the second extraction are dried over sodiumsulphate, filtered and concentrated. The title compound is obtained as acolourless oil from the residue by means of flash chroma-tography (SiO260F). Rf=0.29 (1:1 EtOAc-heptane+1% ACOH); Rt=4.31 (gradient I).

The starting materials are prepared as follows:

m)4(S)-(3-Cyano-2,2-dimethyl-pronyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

A mixture of 2.04 g of4(S)-(3-methanesulfonyloxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester and 2.17 g of sodium cyanide in 12 ml ofdimethylsulfoxide is heated to 135° C. for 15 hours. The mixture iscooled to room temperature and diluted with water and ethyl acetate. Thelayers are separated and the aqueous layer is extracted with ethylacetate. The combined organic layers are dried over sodium sulphate,filtered and concentrated. The title compound is obtained as acolourless oil from the residue by means of flash chromatography (SiO260F). Rf=0.32 (1:1 EtOAo-heptane); Rt=4.82 (gradient I).

n)4(S)-(3-Methanesulfonyloxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a solution of 1.55 g of4(S)-(3-hydroxy-2,2-dimethyl-propyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester [177198-40-2] in 22 ml of methylene chloride atroom temperature under argon is added 3.49 ml of triethylamine and 0,855ml of methanesulfonyl chloride. The mixture is stirred at roomtemperature for 13 hours. The reaction is quenched by addition of 35 mlof 0.5M HCl. The mixture is extracted with methylene chloride. Theorganic layer is concentrated, dried over sodium sulphate andconcerntrated. The crude title compound is obtained as an orange oil.Rf=0.52 (1:1 EtOAo-heptane); Rt=3.64 (gradient I).

Alternative Method (II) for the Synthesis of Compound 1 g:

To a solution of 8.624(S)-(4-hydroxy-2,2-dimethyl-butyl-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester [177198-37-7] in 193 ml of acetonitrile and 193 mlof carbon tetrachloride is added a solution of 37.4 of sodium periodateand 645 mg of ruthenium trichloride monohydrate in 374 ml of water. Thebiphasic mixture is rigorously stirred at room temperature for 6 hours.The layers are separated and the aqueous layer is extracted withmethylene chloride (2×). The combined organic layers are dried oversodium sulphate, filtered and concentrated. The title compound isobtained as a colourless oil from the residue by means of flashchromatography (SiO2 60F). Rf=0.29 (1:1 EtOAc-heptane+1% AcOH); Rt=4.31(gradient I).

According to the processes described in Example 1, the followingcompounds are prepared in an analogous manner:

Examples: 21-(5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-morpholin-4-yl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R;S)-yl]-carbamic acid methyl esterdihydrochloride 3{-[5(S)-Amino-7-(9-aza-bicyclo[3.3.1]non-9-yl)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R.S)-yl}-carbamic acid methyl esterdihydrochloride 4{1-[5(S)-Amino-7-(cis-2,6-dimethyl-piperidin-1-yl)-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester dihydrochloride 5{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(3(R,S)-methyl-piperidin-1-yl)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl esterdihydrochloride 6{1-5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(4-methyl-piperidin-1-yl)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl esterdihydrochloride 7[1-(5(S)-Amino-7-(S)-sec-butylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 8[1-(5(S)-Amino-7-tert-butylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 9[-(5(S)-Amino-6(hydroxy-7-isopropylamino-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 10[1-(5(S)-Amino-7-(R)sec-butylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 11{1-[5(S)-Amino-7-(cyclopropylmethyl-amino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl esterdihydrochloride 12[1-(5(S)-Amino-7-cyclopentylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 13[1-(5(S)-Amino-7-benzylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride 14{1-[5(S)-Amino-6(S)-hydroxy-7-(2(R)-methoxymethyl-pyrrolidin-1-yl)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester dihydrochloride 15{1-[5(S)-Amino-7-(1-carbamoyl-ethylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl esterdihydrochloride 16{1-[7-(3-Acetylamino-pyrrolidin-1-yl)-5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester dihydrochloride 17[1-(5(S)-Amino-7-diethylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterdihydrochloride

Example 18{1-[5(S)-Amino-7-(2,2-dimethyl-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride

Analogously to Method A, 0.033 g of{1-[5(S)-tert-butoxycarbonylamino-7-(2,2-dimethyl-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester are used to prepare the title compound which isobtained as a white solid. Rf=0.41 (200:40:1dichloromethane-methanol-25% conc. ammonia); Rt=3.35 (gradient I).

The starting materials are prepared as follows:

a){1-[5(S)-tert-butoxycarbonylamino-7-(2,2-dimethyl-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester

To a solution of 0.030 g of[1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester in 0.6 ml of ethyl acetate at room temperature underargon is added 0.6 ml of saturated aqueous sodium carbonate solution.The mixture is stirred for 15 minutes at room temperature and and 0.011ml of pivaloyl chloride are added. The mixture is stirred at roomtemperature for 1.5 hours. The layers are separated and the aqueouslayer is extracted with ethyl acetate (2×). The combined organic layersare dried over sodium sulphate, filtered and concentrated. The titlecompound is obtained as a beige oil from the residue by means of flashchromatography (SiO2 60F). Rt=4.46 (gradient I).

b)[1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

A mixture of 0.37 g of[1-(7-azido-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester and 75 mg of 10% Pd/C in 15 ml of methanol ishydrogenated at room temperature for 2 hours. The solid is removed byfiltration over Hyflo® and the solution is concentrated. The titlecompound is obtained as a yellow oil from the residue by means of flashchromatography (SiO2 60F). Rf=0.12 (200:40:1dichloromethane-methanol-25% conc. ammonia); Rt=3.43 (gradient I).

c)[1-(7-Azido-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester

To a solution of 0.50 g of[1-(5(S)tert-butoxycarbonylamino-3,3-dimethyl-5-(R)-oxiranyl-pentanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester (Example 1b) in 10 ml of methanol at room temperatureis added 0.17 g of sodium azide and 0.10 g of ammonium chloride. Themixture is stirred at reflux for 9 hours. The mixture is poured into iceand water and extracted with tert-butyl methyl ether (2×). The combinedorganic layers are washed with water and brine, dried over sodiumsulphate, filtered and concentrated. The title compound is obtained as ayellow oil from the residue by means of flash chromatography (SiO2 60F).Rf=0.3 (2:1 EtOAc-heptane); Rt=4.41 (gradient I).

Example 19(1-{5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-[2-methyl-2-tetrahydro-pyran-4-yl)-propionylamino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamicacid methyl ester hydrochloride

Analogously to Method A, 0.044 9 of(1-{5(S)-tert-butoxycarbonylamino-6-(hydroxy-3,3-dimethyl-7-[2-methyl-2-(tetrahydro-pyran-4-yl)-propionylamino]-heptanoyl}-,2,3,4-tetrahydro- quinolin-3(R,S)yl)-carbamic acid methyl ester areused to prepare the title compound which is obtained as a white solid.Rf=0.43 (200:40:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.28(gradient I).

The starting material is prepared as follows:

a)(1-{5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-7-[2-methyl-2-(tetrahydro-pyran-4yl)-propionylamino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamicacid methyl ester

To a solution of 0.017 g of 2-methyl-2-(tetrahydro-pyran-4-yl)-propionicacid in 1 ml of methylene chloride under argon at 0° C. is added 0.021ml of 1-chloro-N,N-2-trimethylpropenylamine. The mixture is stirred for1 hour, concentrated, and the residue dissolved in 0.6 ml ethyl acetate.This solution is added to a mixture of 0.030 g of[1-(7-amino-5(S)tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester(Example 18b) in 0.6 ml of ethyl acetate and 0.6 ml of saturated aqueoussodium carbonate. After stirring at room temperature for 1.5 hours, thelayers are separated and the aqueous layer is extracted with ethylacetate (2×). The combined organic layers are dried over sodiumsulphate, filtered and concentrated. The title compound is obtained as abeige oil from the residue by means of flash chromatography (SiO2 60F).Rt=4.32 (gradient I).

According to the processes described in Examples 18 and 19, thefollowing compounds are prepared in an analogous manner:

Examples: 20{1-[5(S)-Amino-7-(2-cyclohexyl-2-methyl-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heotanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 21(1-{5(S)-Amino-6(S)-hydroxv-3,3-dimethyl-7-[(1-phenyl-cyclobutanecarbonyl)-amino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methylester hydrochloride 22{1-[5(S)-Amino-7-(2,2-dimethy-hexanoylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 23[1-(5(S)-Amino-7-{[1-(4-chloro-pheny)-cyclobutanecarbonyl]-amino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester hydrochloride 24{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-methyl-2-morpholin-4-yl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester dihydrochloride 25(1-{5(S)-Amino-7-[2-(3-fluoro-phenyl)-2-methyl-propionylamino]-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 26(1-{5(S)-Amino-7-[(1-cyclohexyl-cyclobutanecarbonyl)-amino]-6(S)-hydroxy-3,3-dimethyl-heptanol}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 27{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-methyl-2-pyridin-3-yl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester dihydrochloride 28{1-[5(S)-Amino-4-(3-chloro-2,2-dimethyl-propionylamino)-6(S)-hydroxy-3,3-dimethylheptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methylester hydrochloride 29{1-[7-(2-Acetylamino-2-methyl-propuinylamino)-5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester hydrochloride 30(1-{5(S)-Amino-6(S)-hydrozy-3,3-dimethyl-7-[(1-trifluoromethyl-cyclobutanecarbonyl)-amino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 31{1-[5(S)-Amino-7-(2-cyclohexyloxy-2-methyl-propionylamino)-6(S)-hydrozy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester hydrochloride 32{1-[5(S)-Amino-6(S)-hydroxy-7-(2-methoxy-2-methyl-propionylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 33{1-]5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-methyl-2-piperidin-1-yl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester dihydrochloride 34(1-[5(S)-Amino-6(S)-hydrozy-3,3-dimethyl-7-[(1-methyl-cyclohexanecarbonyl)-amino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methylester hydrochloride 35(1-{5(S)-Amino-6(S)-hydroxy-7-[2-(1H-indol-3-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 36{1-[5(S)-Amino-6(S)-hydroxy-7-(2(R)-methoxy-propionylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 37(1-{7-[(Adamantane-1-carbonyl)-amino]-5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methylester hydrochloride 38(1-{5(S)-Amino-7-[(2,2-dimethyl-propionyl)-hydroxy-amino]-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methylester hydrochloride 39{1-[5(S)-Amino-7-(3,3-dimethyl-ureido)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl ester hydrochloride40[1-(5(S)-Amino-7-benzoylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester hydrochloride41{1-[7-(Acetyl-methyl-amino)-5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl ester hydrochloride42{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(3,3,3-trifluoro-2(R)-methoxy-2-phenyl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride 43{1-[7-(N-Acetyl-hydrazino)-5(S)-Amino-6(S)-hydrozy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl esterdihydrochloride 44{1-[5(S)-Amino-6(S)-hydroxy-7-(2-methoxy-3-phenyl-propionylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 45{1-[5(S)-Amino-7-(3-cyclohexyl-2-methoxy-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester hydrochloride 46(1-{5(S)-Amino-6(S)-hydroxy-7-[2-(1H-imidazol-4-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 47{1-[5(S)-Amino-7-(2,2-dimethyl-4-methylamino-butyrylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester dihydrochloride 48(1-{5(S)-Amino-6(S)-hydroxy-7-[(2(S)-hydroxy-(S)-cyclopentanecarbonyl)-amino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 49(1-{5(S)-Amino-6(S)-hydroxy-7-[2-(1,2-dihydro-spiro[3H-indole-3,4′-piperidin]-1′-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester dihydrochloride

50(1-{5(S)-Amino-6(S)-hydroxy-7-[2-(cis-4-hydroxy-cyclohex-1-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride

The starting materials are prepared as follows:

a) 2-(cis-4-Hydroxy-cyclohexyl)-2-methyl-propionic acid

0.200 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionic acid methylester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithiumhydroxide solution are added and the mixture is stirred for 16 hours atroom temperature. The reaction mixture is then neutralised with 1M HCland concentrated by evaporation. The title compound is identified fromthe residue by means of flash chromatography (SiO2 60F) based on its Rfvalue.

b) 2-(cis-4-Hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester and2-(trans-4-Hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester

A solution of 2.0 g of2-(cis/trans-4-hydroxy-cyclohexyl)-2-methyl-propionic acid in 40 ml ofmethanol is cooled to 0° C. 20 ml of a 2M trimethysilyidiazomethanesolution in hexanes are added dropwise and the reaction solution is leftto stand at room temperature for 1 hour. The solution is concentratedunder reduced pressure and the residue taken up in ethyl acetate. Thesolution is washed with saturated aqueous sodium carbonate solution andbrine, dried over sodium sulphate and concentrated by evaporation. Theresidue is purified by flash chromatography (SiO2 60F) to provide thetitle compounds as colourless oils, the cis isomer eluting first. Rf(cis)=0.11 (1:3 EtOAc-heptane); Rf (brans)=0.09 (1:3 EtOAc-heptane).

c) 2-(cis/trans-4-Hydroxy-cyclohexyl)-2-methyl-propionic acid

2.690 g of 2-(4-hydroxy-phenyl)-2-methyl-propionic acid (29913-51-7) aredissolved in 20 ml of water and 30 ml of 1M NaOH solution. 0.200 g ofRaney-Nickel are added and the reaction mixture is hydrogenated at 50bar and 150° C. for 24 hours. The catalyst is removed by filtration overHyflo and the filtrate is concentrated by evaporation. The residue istaken up in 200 ml of water and the solution neutralized with 1M HCl topH 6. The reaction mixture is then extracted with dichloromethane (2×200ml) and ethyl acetate (2×20 ml) and the combined organic phases aredried over sodium sulphate and concentrated by evaporation to providethe title compounds as a ca. 1:4 mixture of cis/trans-isomers. The whitesolid is used for the next step without further purification.

51 (1-{5(S)-Amino-6(S)-hydroxy-7-[2-(trans-4-hydroxy-cyclohex-1-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetra-hydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride 52(1-{5(S)-Amino-6(S)-hydroxy-7-[2-(cis-4-methoxy-cyclohex-1-yl)-2-methyl-propionylamino]3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride

The starting materials are prepared as follows:

a) 2-cis-4-Methoxy-cyclohexyl)-2-methyl-propionic acid

0.200 g of 2-(cis-4-methoxy-cyclohexyl)-2-methyl-propionic acid methylester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithiumhydroxide solution is added and the mixture is stirred for 16 hours atroom temperature. The reaction mixture is then neutrlised with 1M HCland concentrated under reduced pressure. The title compound isidentified from the residue by means of flash chromatography (SiO2 60F)based on its Rf value.

b) 2-(cis-4-Methoxy-cyclohexyl)-2-methyl-propionic acid methyl ester

0.500 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionic acid methylester (Example 50b) are dissolved in 5 ml of dry tetrahydrofuran. 0.120g of sodium hydride (60% dispersion) is added in portions and themixture stirred at 40° C. for 1 hour. Methyl iodide (0.233 ml) is addedand the mixture heated to 40° C. for 5 hours. The reaction mixture isthen cooled to room temperature, quenched with 5 ml of water andextracted with tert-butyl methyl ether (2×50 ml). The combined organicphases are dried over sodium sulphate and concentrated by evaporation.The title compound is identified from the residue by means of flashchromatography (SiO2 60F) based on its Rf value.

53 (1-{5(S)-Amino-6(S)-hydroxy-7-[2-(trans-4-methoxy-cyclohex-1-yl-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydro-chloride 54{-[5(S)-Amino-7-(2-cyclohexyl-2(R)-methoxy-acetylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl ester hydrochloride

The starting material is prepared as follows:

a) (R)-Cyclohexyl-methoxy-acetic acid

An autoclave is charged with a solution of 1.00 g of(R)-α-methoxy-phenyl acetic acid in 20 ml methanol. 0.100 g of Nishimuracatalyst are added and the miture is hydrogenated at 4 bar and 20° C.for 1 hour. The mixture is filtered over Hyflo and the filtrateconcentrated by evaporation to provide the title compound as acolourless oil. The crude material is used without further purification.Rf=0.84 (150:54:10:1 dichloromethane-methanol-water-acetic acid)

55{1-[5(S)-Amino-6(S)hydroxy-7-(2(R)-methoxy-2-phenyl-acetylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 56 {1-[5(S)-Amino6(S)-hydroxy-7-(2(R)-methoxy-3,3-dimethyl-butyrylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester hydrochloride 57{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(3,3,3-trifluoro-2-methoxy-2-trifluoromethyl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl ester hydrochloride 58{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(3,3,3-trifluoro-2(R)-methoxy-2-methyl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride 59{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(3,3,3-trifluoro-2(S)-methoxy-2-methyl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride 60{1-[5(S)-Amino-7-(2-cyclohexyl-3,3,3-trifluoro-2(R)-methoxy-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride 61{1-[5(S)-Amino-7-(2-phenyl-2(R)-methoxy-propionylamino)-6(S)-hydroxy-3,3,-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 62{1-[5(S)-Amino-7-(2-cyclohexyl-2(R)-methoxy-propionylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acidmethyl ester hydrochloride 63(1-{5(S)-Amino-6(S)-hydroxy-7-[(1-methoxy-cyclopentanecarbonyl)-amino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 64(1-{5(S)-Amino-6(S)-hydroxy-7-[(1-methoxy-cyclohexanecarbonyl)-amino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acidmethyl ester hydrochloride 74{1[5(S)-Amino-6(S)-hydroxy-3,3-dimetyl-7-(2-methyl-2-piperidin-3(R,S)-yl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester dihydrochloride 75(1-{5(S)Amino-6(S)-hydroxy-3,3-dimethyl-7-[2-methyl-2-(1-methyl-piperidin-3(R,S)-yl)-propionylamino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamicacid methyl ester dihydrochloride

The starting materials are prepared as follows:

a) 2-Methyl-2-(1-methyl-piperidin-3(R,S)-yl)-propionic acid

0.200 g of 2-methyl-2-(1-methyl-piperidin-3(R,S)-yl)-propionic acidmethyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueouslithium hydroxide solution are added and the mixture is stirred for 16hours at room temperature. The reaction mixture is neutralised with 1MHCl and extracted with ethyl acetate (3×50 ml). The organic phases arecombined and concentrated by evaporation. The residue is purified bymeans of flash chromatography (SiO2 60F) to provide the title compoundas a colourless oil. Rf 0.15 (150:54:10:1dichloromethane-methanol-acetic acid-water).

b) 2-Methyl-2-(1-methyl-piperidin-3(R,S)-yl)-propionic acid methyl ester

0.370 g of 2-methyl-2-piperidin-3(R,S)-yl-propionic acid methyl esterhydrochloride are dissolved in 0.5 ml of 3M NaOH. 2 ml of formic acidand 0.19 ml of formaldehyde (35% aqueous solution) are added and thereaction solution is warmed to 60° C. for 20 hours. The solution iscooled to room temperature, neutralised with 3M NaOH to pH 8-9 andextracted with dichloromethane (3×10 ml). The combined organic phasesare washed with water (10 ml), dried over sodium sulphate andconcentrated by evaporation. The residue is purified by means of flashchromatography (SiO2 60F) to provide the title compound as a colourlessoil. Rf 0.19 (200:20:1 dichlormethane-methanol-25% conc. ammonia).

c) Methyl 2-methyl-2-piperidin-3(R,S)-ylpropionate hydrochloride

0.115 g of methyl 2-methyl-2-pyridinylpropionate (CAS 476429-23-9) isdissolved in an autoclave in 5 ml of methanol. The solution is admixedwith 0.35 ml of 1.2M HCl in methanol and 0.012 g of platinum(IV) oxide,and the reaction mixture is hydrogenated at 4 bar and 23° over 46 hours.The catalyst is filtered off through Hyflo and the filtrate isconcentrated by evaporation to give the crude titel compound which isused directly in the next step.

76{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-methyl-2-piperidin-2(R,S)yl-propionylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester dihydrochloride 77(1-{5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-[2-methyl-2-(1-methyl-piperidin-2(R,S)-yl)-propionylamino]-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamicacid methyl ester dihydrochloride 78(1-{5(S)-Amino-6(S)-hydroxy-7-[2(R,S)-(trans-2-hydroxy-cyclohexyl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride

The starting material is prepared as follows:

a)trans-2-[2-tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-methyl-propionicacid

Imidazole (0.310 g) is added to a solution of 0.337 gtrans-(2-2-hydroxy-cyclohexyl)-2-methyl propionic acid (34440-72-7) and0.682 g tert-butyl-dimethyl-chlarosilane in 7 ml of dryN,N-dimethylformamide. The mixture is left to stand at room temperaturefor 2 hours and is then warmed to 50° for 12 hours. The reaction mixtureis poured onto water (30 ml) and the mixture is extracted withtert-butyl methyl ether (2×50 ml). The combined organic phases arewashed with saturated aqueous sodium bicarbonate solution (30 ml) andbrine (30 ml), dried over sodium sulphate and concentrated under reducedpressure. The residue is taken up in 9 ml of methanol and 3 ml oftetrahydrofuran and the resulting mixture is treated for 1 hour at roomtemperature.with a 10% aqueous potassium carbonate solution (3 ml). Thereaction solution is concentrated under reduced pressure to half of theinitial volume and the pH is adjusted to 6 with 1M HCl. The mixture isextracted with tert-butyl methyl ether (2×60 ml) and the combinedorganic phases are washed with brine, dried over sodium sulphate andconcentrated under reduced pressure. The residue is purified by means offlash chromatography (SiO2 60F) to provide the title compound as whitesolid. Rf 0.64 (1:2 EtOAc-heptane).

79 (1-{5(S)-Amino-6(S)-hydroxy-7-[2(R,S)-(3(S)-hydroxy-cyclohex-1(R)-yl)-2-methyl-propionylamino]-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydro-chloride

The starting materials are prepared as follows:

a) 2-(3(S)-Hydroxy-cyclohex-1(R)-yl)-2-methyl-propionic acid

1.00 g of 2-(cis-3-hydroxy-cyclohexyl)-2-methyl-propionic acid ethylester are dissolved in 30 ml of methanol. 30 ml of a 1M aqueous lithiumhydroxide solution are added and the mixture is stirred for 16 hours atroom temperature. The reaction mixture is neutralised with 1M HCl andconcentrated by evaporation. The title compound is identified from theresidue by means of flash chromatography (SiO2 60F) based on its Rfvalue.

b) 2-(3(S)-Hydroxy-cyclohex-1(R)-yl)-2-methyl-propionic acid ethyl ester

3 ml of 1M tetrabutylammonium fluoride solution in tetrahydrofuran areadded to a solution of 1.00 g of2-[3(S)-(tert-butyl-dimethylsilanyloxy)-cyclohex-(1R)-yl]-2-methyl-propionicacid ethyl ester in 3 ml of tetrahydrofuran at 0° C. The reaction isleft to stand at room temperature for 1 hour and is then diluted withtert-butyl methyl ether (20 ml) and washed with water (20 ml) and brine(20 ml). The organic layer is dried over sodium sulphate andconcentrated by evaporation. The title compound is identified from theresidue by means of flash chromatography (SiO2 60F) based on its Rfvalue.

c)2-[3(S)-(tert-Butyl-dlimethylsilanyloxy)-cyclohex-1(R)-yl]-2-methyl-propionicacid ethyl ester

A solution of 21 ml lithium diisopropylamide (ca. 1M intetrahydrofuran/hexanes) is cooled to −78° b. A solution of 3.72 g[3(S)-(tert-butyl-dimethyl-silanyl-oxy)-cyclohex-1(R)-yl]-acetic acidethyl ester (197091-18-2) in 20 ml of tetrahydrofuran is added dropwiseover a period of 15 minutes while maintaining the temperature at −78° C.The reaction solution is stirred for 30 minutes at −78° C. and methyliodide (1.31 ml) is added in one portion. The reaction mixture is warmedto 0° C. over a period of 30 minutes and is then cooled again to −78° C.Lithium diisopropylamide-solution (21 ml) is added dropwise over aperiod of 15 minutes and the reaction mixture is stirred for 30 minutesat −78° C. 1.31 ml Methyl iodide are added in one portion and thereaction mixture is warmed to room temperature over a period of 16hours. The reaction mixture is quenched with 0.1M HCl (50 ml) and isthen extracted with tert-butyl methyl ether (3×50 ml). The combinedorganic phases are washed with brine (50 ml), dried over sodium sulphateand concentrated by evaporation. The title compound is identified fromthe residue by means of flash chromatography (SiO2 60F) based on its Rfvalue.

80 {1-[5(S)-Amino-6(S)-hydroxy-7-(2-imidazol-1-yl-2-methyl-propionylamino)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quino-lin-3(R,S)-yl}-carbamic acid methyl ester dihydrochloride

The starting material is prepared as follows:

a) 2-Imidazol-1-yl-2-methyl-propionic acid

1.54 g of 2-imidazol-1-yl-2-methyl-propionic acid ethyl ester(73828-88-3) are dissolved in 20 ml of methanol. 20 ml of a 3M NaOH areadded and the mixture is stirred for 16 hours at 60° C. The reactionmixture is then neutralised with 1M HCl and concentrated by evaporation.The title compound is identified from the residue by means of flashchromatography (SiO2 60F) based on its Rf value.

81 {1-[5(S)-Amino-7-(2-cyano-2,2-dimethyl-acetylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}- carbamicacid methyl ester hydrochloride 82(1-{7-[2-(trans-4-Acetylamino-cyclohexyl)-2-methyl-propionyl-amino]-5(S)-amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydro-chloride

The starting materials are prepared as follows:

a) trans-2-(4-Acetylamino-cyclohexyl)-2-methyl-propionic acid

0.200 g of trans-2-(4-acetylamino-cyclohexyl)-2-methyl-propionic acidmethyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueouslithium hydroxide solution are added and the mixture is stirred for 16hours at room temperature. The reaction mixture is neutralised with 1MHCl and extracted with ethyl acetate (3×50 ml)—the combined organicphases are concentrated by evaporation. The title compound is identifiedfrom the residue by means of flash chromatography (SiO2 60F) based onits Rf value.

b) trans-2-(4-Acetylamino-cyclohexyl)-2-methyl-propionic acid methylester

A round bottom flask is charged with 0.422 g oftrans-2-(4-azido-cyclohexyl)-2-methyl-propionic acid methyl ester. 0.71ml of thiocetic acid are added and the solution is stirred for 1 hour atroom temperature. After completion of the reaction, the reaction mixtureis concentrated by evaporation. The title compound is identified fromthe residue by means of flash chromatography (SiO2 60F) based on its Rfvalue.

c) trans-2-(4-Azido-cyclohexyl)-2-methyl-propionic acid methyl ester

Sodium azide (0.761 g) is added to a solution of 0.898 9 ofcis-2-(4-methanesulfonyloxy-cyclohexl)-2-methyl-propionic acid methylester in 7 ml of N,N-dimethylformamide. The reaction mixture is warmedto 100° C. for 16 hours. The mixture is cooled to room temperature,diluted with 20 ml of water and extracted with tert-butyl methyl ether(3×30 ml). The combined organic phases are washed with brine (20 ml),dried over sodium sulphate and concentrated by evaporation. The titlecompound is identified from the residue by means of flash chromatography(SiO2 60F) based on its Rf value.

d) cis-2-(4-Methanesulfonyloxy-cyclohexl)-2-methyl-propionic acid methylester

A solution of 1.00 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionicacid methyl ester (Example 50b), 1.38 ml triethylamine and 0.061 g of4-dimethylaminopyridine in 20 ml of dichloromethane is cooled to 0° C.Methanesulfonychloride (0.50 ml) is added and the solution is left tostand at room temperature for 16 hours. The solution is poured ontosaturated aqueous sodium hydrogen carbonate solution and the phases areseparated. The aqueous phase is extracted with dichloromethane (2×50ml)—the combined organic phases are washed with brine (50 ml), driedover sodium sulphate and concentrated by evaporation.

The title compound is identified from the residue by means of flashchromatography (SiO2 60F) based on its Rf value.

83 (1-{7-[2-(cis-3-Acetylamino-cyclohexyl)-2-methyl-propionylamino]-5(S)-amino-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetra-hydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride

The starting materials are prepared according to the processes describedin Example 152 starting from2-(3(S)-hydroxy-cyclohex-1(R)-yl)-2-methyl-propionic acid ethyl ester(Example 79b).

84 {1-[5(S)-Amino-7-(2,2-difluoro-2-phenyl-acetylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}- carbamicacid methyl ester hydrochloride 85{1-[5(S)-Amino-7-(2-cyclohexyl-2,2-difluoro-acetylamino)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methyl ester hydrochloride 86(1-{5(S)-Amino-7-[2,2-difluoro-2-(tetrahydro-pyran-4-yl)-acetyl-amino]-6(S)-hydroxy-3,3-dimethyl-heptanoyl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamic acid methyl ester hydrochloride

Example 65{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-oxo-piperidin-1-yl)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamicacid methyl ester hydrochloride

A solution of 0.051 g of(1-(3,3-dimethyl-4-[2-oxo-5(S)-(2-oxo-piperidin-1-ylmethyl)-oxazolidin-4(S)-yl]-butyryl}-1,2,3,4-tetrahydro-quinolin-(R,S)-yl)-carbamicacid methyl ester and 0.050 g lithium hydroxide hydrat in 1.5 ml ethanolund 1.5 ml wasser is stirred at 100° C. for 2 hours. The reactionmixture is cooled to room temperature, poured into ice and water andextracted with ethyl acetate (3×). The combined organic layers are driedover sodium sulphate, filtered and concentrated. The free base of thetitle compound is identified from the residue by means of flashchromatography (SiO2 60F) based on its Rf value. This is dissolved in 1ml dioxane, diluted with 0.040 ml 4N HCl (in dioxane), frozen in liquidnitrogen and lyophilized to give the title compound.

The starting material is prepared as follows:

a)(1-{3,3-dimethyl-4-[2-oxo-5(S)-(2-oxo-piperidin-1-ylmethyl)-oxazolidin-4(S)-yl]-butyryl}-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl)-carbamicacid methyl ester

A mixure of 0.115 g piperidin-2-one and 0.136 g potassium tert-butoxidein 3 ml dimethylsulfoxide is stirred at room temperature for 30 minutes,charged with 0.256 g[1-(5(S)-tert-butoxycarbonylamino-3,3-dimethl-5-(R)-oxiranyl-pentanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamicacid methyl ester (Example 1b), and then stirred overnight. The reactionmixture is poured into a mixture of ice and water and extracted withtert-butyl methyl ether (2×). The combined organic layers are washedwith water and brine, dried over sodium sulphate, filtered andconcentrated. The title compound is identified from the residue by meansof flash chromatography (SiO2 60F) based on its Rf value.

According to the process described in Example 65, the followingcompounds are prepared in an analogous manner.

Examples: 66{1-[5(S)-Amino-7-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 67{1-[5(S)-Amino-6(S)-hydroxy-7-(4(R)-hydroxy-2-oxo-pyrrolidin-1-yl)-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 68{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-oxo-tetrahydro-pyrimidin-1-yl)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride

Example 69{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(propane-2-sulfonylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}carbamicacid methyl ester hydrochloride

0.007 ml Propan-2-sulfonyl chlorid are added to a solution of 0.026 g[1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester(Example 18b) and 0.007 ml triethylamine in 1 ml dichlormethane at 0° C.After 5 hours, the reaction mixture is concentrated. The intermediateN-Boc derivative is identified from the residue by means of flashchromatography (SiO2 60F) based on its Rf value. This is dissolved in0.82 ml 4N HCl (in dioxane), stirred for 4 hours and concentrated. Theresidue is dissolved in 0.5 ml tert-butanol, frozen in liquid nitrogenand lyophilized to give the title compound which is identified from theresidue based on its Rf value.

According to the process described in Example 69, the followingcompounds are prepared in an analogous manner:

Examples: 70[1-(5(S)-Amino-7-cyclopropanesulfonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl-carbamic acid methyl esterhydrochloride 71[1-(5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-phenylmethanesulfonylamino-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterhydrochloride 72{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(thiophene-2-sulfonylamino)-heptanoy1]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl-carbamic acid methyl esterhydrochloride 73[1-(5(S)-Amino-7-benzenesulfonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl esterhydrochloride 87{1-[5(S)-Amino-6(S)-hydroxy-3,3-dimethyl-7-(2-methyl-propane-2-sulfonylamino)-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride 88{1-[5(S)-Amino-7-(2-cyclohexyl-propane-2-sulfonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl]-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl}-carbamic acid methylester hydrochloride

The starting materials are prepared as follows:

a) 2-Cyclohexyl-propane-2-sulfonyl chloride

2 mmol of phosphoroxytrichloride are added to a solution of 1 mmol of2-cyclohexyl-propane-2-sulfonic acid in acetonitrile and the reactionmixture is heated to reflux for 2 hours. The reaction mixture is cooledto room temperature, carefully quenched by the addition of water andextracted with tert-butyl methyl ether. The organic phase is dried oversodium sulphate and concentrated by evaporation. The crude titelcompound is used without further purification.

b) 2-Cyclohexyl-propane-2-sulfonic acid

10 ml of an aqueous hydrogen peroxide solution (30% wt) are added to astirred solution of 1 mmol of 2-cyclohexyl-propane-2-thiol in acetic andthe mixture is then heated at 60° C. overnight. The reaction mixture iscooled to room temperature and the solvent removed under reducedpressure. The crude titel compound is used without further purification.

c) 2-Cyclohexyl-propane-2-thiol

1 mmol of thiourea is added to a stirred solution of 1 mmol of(1-bromo-1-methyl-ethyl)-cyclohexane [BRN 2424910] in methanol and themixture is stirred for 12 hours at room temperature. The solvent isremoved under reduced pressure and the residue is then suspended in 10ml of 2N NaOH and heated at 60° C. for 3 hours. The reaction mixture iscooled to room temperature and extracted with tert-butyl methyl ether(3×). The combined organic phases are dried over sodium sulphate andconcentrated by evaporation. The crude titel compound is used withoutfurther purification.

1. Compound of the formula

where R₁ is a) hydrogen, amino or hydroxyl; or is b) C₁-C₈-alkyl,C₃-C₈-cycloalkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, aryl-C₀-C₄-alkylor heterocyclyl-C₀-C₄-alkyl, which radicals may be substituted by 1-4,C₁-C₈-alkyl, halogen, cyano, oxide, oxo, trifluoromethyl, C₁-C₈-alkoxy,C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl; R₂ is a) C₁-C₈-alkyl,C₃-C₈-cycloalkyl, C₁-C₈-alkylsulphonyl, C₃-C₈-cycloalkylsulphonyl,aryl-C₀-C₈-alkylsulphonyl, heterocyclylsulphonyl,C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl, aryl-C₁-C₈-alkanoyl,aryl-C₃-C₈-cycloalkanoyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl,optionally N-mono- or N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl,aryl-C₀-C₄-alkyl or heterocyclyl-C₀-C₄-alkyl, which radicals may besubstituted by 1-4 C₁-C₈-alkyl, C₃-C₁₂-cycloalkyl, C₃-C₈-cycloalkoxy,amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, C₁-C₆-alkanoylamino,C₁-C₆-alkoxycarbonylamino, halogen, oxo, cyano, hydroxyl, oxide,trifluoromethyl, C₁-C₈-alkoxy, optionally N-mono- orN,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, optionally esterifiedcarboxyl, C₁-C₆-alkylenedioxy, aryl or heterocyclyl; or is b) togetherwith R₁ and the nitrogen atom to which they are bonded a saturated orpartly unsaturated 4-8-membered heterocyclic ring which may contain anadditional nitrogen, oxygen or sulphur atom or a —SO— or —SO2-group, inwhich case the additional nitrogen atom may optionally be substituted byC₁-C₈-alkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, aryl or heterocyclylradicals, and this heterocyclic ring may be part of a bicyclic ortricyclic ring system having a total of up to 16 members and the secondring may also contain a nitrogen, oxygen or sulphur atom or a —SO— or—SO2-group, and the nitrogen atom in the second ring may optionally besubstituted by C₁-C₈-alkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, arylor heterocyclyl radicals and all ring systems mentioned may besubstituted by 1-4 C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₁-C₈-alkylsulphonyl,C₃-C₈-cycloalkylsulphonyl, aryl-C₀-C₈-alkylsulphonyl,heterocyclylsulphonyl, C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl,aryl-C₁-C₈-alkanoyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, optionallyN-mono- or N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, halogen,hydroxyl, oxide, oxo, trifluoromethyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,C₁-C₈-alkoxycarbonylamino, C₁-C₈-alkanoylamino, C₁-C₈-alkylamino,N,N-di-C₁-C₈-alkylamino, aryl-C₀-C₄-alkyl, aryloxy-C₀-C₄-alkyl,aryl-C₀-C₄-alkyl-C₁-C₈-alkoxy, aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy,heterocyclyl-C₀-C₄-alkyl, heterocyclyloxy-C₀-C₄-alkyl,heterocyclyl-C₀-C₄-alkyl-C₁-C₈-alkoxy orheterocyclyloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy; R₃ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl; R₄ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl; R₅ are each independentlyhydrogen or C₁-C₈-alkyl or, together with the carbon atom to which theyare bonded, are a C₃-C₈-cycloalkylidene radical; R₆ is one oxygen atomor two hydrogen atoms; R is optionally substituted arylamino,N-aryl-N-((lower alkoxy)(lower alkyl))amino, N-aryl-N-aryl(loweralkyl)amino or heterocyclyl bonded via a ring nitrogen atom; or salt orprodrug thereof, or where one or more atoms are replaced by theirstable, non-radioactive isotopes.
 2. Compound according to claim 1,where R₁ a) is hydrogen; or is b) C₁-C₈-alkyl, C₃-C₈-cycloalkyl,C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, aryl-C₀-C₄-alkyl orheterocyclyl-C₀-C₄-alkyl, which radicals may be substituted by 1-4C₁-C₈-alkyl, halogen, cyano, oxide, oxo, trifluoromethyl, C₁-C₈-alkoxy,C₁-C₈-alkoxycarbonyl, aryl or heterocyclyl; R₂ is a) C₁-C₈-alkyl,C₃-C₈-cycloalkyl, C₁-C₈-alkylsulphonyl, C₃-C₈-cycloalkylsulphonyl,aryl-C₀-C₈-alkylsulphonyl, heterocyclylsulphonyl,C₃-C₈-cycloalkyl-C₁-C₈-alkanoyl, aryl-C₁-C₈-alkanoyl,aryl-C₃-C₈-cycloalkanoyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl,optionally N-mono- or N,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl,aryl-C₀-C₄-alkyl or heterocyclyl-C₀-C₄-alkyl, which radicals may besubstituted by 1-4 C₁-C₈-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkoxy,amino, C₁₋₆-alkylamino, di-C₁₋₆-alkylamino, C₀-C₆-alkylcarbonylamino,C₁-C₆-alkoxycarbonylamino, halogen, oxo, cyano, hydroxyl, oxide,trifluoromethyl, C₁-C₈-alkoxy, optionally N-mono- orN,N-di-C₁-C₈-alkylated carbamoyl-C₀-C₈-alkyl, optionally esterifiedcarboxyl, C₁₋₆-alkylenedioxy, aryl or heterocyclyl; or is b) togetherwith R₁ and the nitrogen atom to which they are bonded, a saturated orpartly unsaturated 4-8-membered heterocyclic ring which may contain anadditional nitrogen, oxygen or sulphur atom or a —SO— or —SO2- group, inwhich case the additional nitrogen atom may optionally be substituted byC₁-C₈-alkyl, C₁-C₈-alkanoyl, C₁-C₈-alkoxycarbonyl, aryl or heteroarylradicals, and this heterocyclic ring may be part of a bicyclic ortricyclic ring system having a total of up to 16 members and the secondring may also contain a nitrogen, oxygen or sulphur atom or a —SO— or—SO2- group, and the nitrogen atom in the second ring may optionally besubstituted by C₁-C₉-alkyl, C₁-C₉-alkanoyl, C₁-C₈-alkoxycarbonyl, arylor heterocyclyl radicals, and all ring systems mentioned may besubstituted by 1-4 C₁-C₈-alkyl, halogen, hydroxyl, cyano, oxide, oxo,trifluoromethyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy,C₁-C₈-alkoxycarbonylamino, C₀-C₈-alkylcarbonylamino, C₁-C₈-alkylamino,N,N-di-C₁-C₈-alkylamino, aryl-C₀-C₄-alkyl, aryloxy-C₀-C₄-alkyl,aryl-C₀-C₄-alkyl-C₁-C₈-alkoxy, aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy,heterocyclyl-C₀-C₄-alkyl, heterocyclyloxy-C₀-C₄-alkyl,heterocyclyl-C₀-C₄-alkyl-C₁-C₈-alkoxy orheterocyclyloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy; R₃ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl or C₁-C₈-alkanoyl; R₄ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonylor C₁-C₈-alkanoyl; R₅ are each independentlyhydrogen or C₁-C₈-alkyl, R₆ is oxygen, R is arylamino, N-aryl-N-((loweralkoxy)(lower alkyl))amino, N-aryl-N-aryl(lower alkyl)amino orheterocyclyl bonded via a ring nitrogen atom, in which case theheterocyclyl mentioned, apart from the ring nitrogen atom via which itis bonded, may contain further ring heteroatoms selected from oxygen,nitrogen, nitrogen substituted by lower alkyl, lower alkanoyl, (loweralkane)sulphonyl or (lower alkoxy)carbonyl, sulphur, and sulphur bondedto 1 or 2 oxygen atoms, or salt or prodrug thereof, or where one or moreatoms are replaced by their stable, non-radioactive isotopes. 3.Compound according to claim 1 of the formula I, where R is a group ofthe formula

in which A is a direct bond, methylene, dimethylene, imino, oxy or thio,R₇ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy- or propyloxymethyl,C₃-C₅-alkenyloxy-C₁-C₄-alkyl, such as allyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxymethoxymethyl or2-methoxyethoxymethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkyl, such asmethoxy- or ethoxycarbonylaminomethyl, C₁-C₄-alkoxyimino-C₁-C₄-alkyl,such as methoxyiminomethyl, phenyl, C₁-C₄-alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl or isopropyloxycarbonyl, cyano,carbamoyl, N—C₁-C₄-alkylcarbamoyl, such as N-methylcarbamoyl,N-ethylcarbamoyl or N-butylcarbamoyl, C₁-C₄-alkoxy-C₁-C₄-alkylcarbamoyl,such as N-(2-methoxyethyl) carbamoyl, C₁-C₄- alkoxy such as propyloxy,C₁-C₄-alkoxy-C₁-C₄-alkoxy such as methoxymethoxy or 2-methoxyethoxy,C₁-C₈-alkanoyloxy such as acetoxy, benzoyloxy,N—C₁-C₄-alkylcarbamoylamino, such as N-methylcarbamoylamino,C₁-C₄-alkanoylamino, such as acetylamino, C₁-C₄-alkoxycarbonylamino,such as methoxycarbonylamino, 3- to 6-membered cycloalkylcarbonylamino,such as cyclopropylcarbonylamino, C₁-C₄- alkoxy-C₁-C₄-alkanoylamino,such as methoxyacetylamino, or 5- or 6-membered N,N-(1-oxo(loweralkylene))amino or N,N-(1-oxo-2-oxa(lower alkylene))amino, such as2-oxopyrrolidin-1-yl or 2-oxooxazolidin-3-yl,N—C₁-C₄-alkylcarbamoylamino, such as methylcarbamoylamino, R₈ ishydrogen, but may also be C₁-C₄-alkyl such as methyl, R₉ is hydrogen orhalogen and R₁₀ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such asmethoxy-C₁-C₄-alkyl, ethoxy-C₁-C₄-alkyl, propyloxy-C₁-C₄-alkyl,isopropyloxy-C₁-C₄-alkyl, butyloxy-C₁-C₄-alkyl, isobutyloxy-C₁-C₄-alkyl,sec-butyloxy-C₁-C₄-alkyl or tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkylis, for example, ethyl, propyl or butyl, and is in particular3-methoxypropyl.
 4. Compound according to claim 1 of the formula

where R, R₁, R₂, R₃, R₄, R₅ and R₆ are each as defined in claim 1 orsalt thereof, in particular pharmaceutically usable salt thereof. 5.Compound according to claim 1 of the formula

where A is methylene, oxy or thio, R₁ is a) hydrogen; or is b)C₁-C₈-alkyl or C₃-C₈-cycloalkyl; R₂ is a) C₁-C₈-alkyl, C₃-C₈-cycloalkyl,C₁-C₈-alkanoyl, heterocyclyl-C₁-C₈-alkanoyl,C₃-C₁₂-cycloalkyl-C₁-C₈-alkanoyl or aryl-C₁-C₈-alkanoyl, which radicalsmay be substituted by 1-4 C₁-C₈-alkyl, C₃-C₈-cycloalkyl,C₃-C₈-cycloalkoxy, C₁₋₆-alkylamino, cyano, halogen, hydroxyl, oxide,C₀-C₆-alkylcarbonylamino, C₁-C₈-alkoxy, oxo, trifluoromethyl or aryl; orb) together with R₁ and the nitrogen atom to which they are bonded, is asaturated or partly unsaturated, 4-8-membered heterocyclic ring whichmay contain an additional nitrogen or oxygen atom, in which case theadditional nitrogen atom may optionally be substituted by C₁-C₈-alkyl orC₁-C₈-alkanoyl, and this heterocyclic ring may be part of a bicyclic ortricyclic ring system having a total of up to 16 members, and the secondring may also contain a nitrogen or oxygen atom, in which case thenitrogen atom of the second ring may optionally be substituted byC₁-C₈-alkyl or C₁-C₈-alkanoyl, and all ring systems mentioned may besubstituted by 1-4 C₁-C₈-alkyl, hydroxyl, cyano, oxide, oxo,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkoxy, C₀-C₈-alkylcarbonylamino,C₁-C₈-alkoxycarbonylamino or aryloxy-C₀-C₄-alkyl-C₁-C₈-alkoxy; R₃ ishydrogen or —C═O)—C₁-C₄-alkyl; R₄ is hydrogen; R₅ are each independentlyC₁-C₄-alkyl, such as methyl, R₇ is C₁-C₄-alkoxycarbonylamino such asmethoxycarbonylamino, ethoxycarbonylamino, propyloxycarbonylamino,isopropyloxycarbonylamino or butyloxycarbonylamino,C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such asmethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, ethoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl,propyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl,isopropyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl orbutyloxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, where C₁-C₄-alkoxy is, for example,methoxy, ethoxy, propyloxy or butyloxy, and C₁-C₄-alkyl is, for example,methyl, ethyl, propyl or butyl, in particular methoxymethoxymethyl,2-methoxyethoxymethyl or 3-methoxypropyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy-C₁-C₄-alkyl,ethoxy-C₁-C₄-alkyl, propyloxy-C₁-C₄-alkyl, isopropyloxy-C₁-C₄-alkyl,butyloxy-C₁-C₄-alkyl, isobutyloxy-C₁-C₄-alkyl, sec-butyloxy-C₁-C₄-alkylor tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkyl is, for example, methyl,ethyl, propyl or butyl, in particular ethoxymethyl or 2-methoxyethyl, orN—C₁-C₄-alkylcarbamoyl, such as N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl or N-butylcarbamoyl, or salt thereof, in particular apharmaceutically usable salt thereof.
 6. Compound according to claim 1for use in a process for the therapeutic treatment of the human oranimal body.
 7. Pharmaceutical preparation comprising, as an activepharmaceutical ingredient, a compound according to claim 1 in free formor as a pharmaceutically usable salt.
 8. Use of a compound according toclaim 1 for the preparation of a pharmaceutical preparation withrenin-inhibiting action.
 9. Use of a compound according to claim 1 forthe preparation of a pharmaceutical preparation for the treatment orprevention of hypertension, heart failure, glaucoma, cardiac infarction,kidney failure or restenosis.
 10. Compound according to claim 2 of theformula I, where R is a group of the formula

in which A is a direct bond, methylene, dimethylene, imino, oxy or thio,R₇ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxy- or propyloxymethyl,C₃-C₅-alkenyloxy-C₁-C₄-alkyl, such as allyloxymethyl,C₁-C₄-alkoxy-C₁-C₄-alkoxy-C₁-C₄-alkyl, such as methoxymethoxymethyl or2-methoxyethoxymethyl, C₁-C₄-alkoxycarbonylamino-C₁-C₄-alkyl, such asmethoxy- or ethoxycarbonylaminomethyl, C₁-C₄-alkoxyimino-C₁-C₄-alkyl,such as methoxyiminomethyl, phenyl, C₁-C₄-alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl or isopropyloxycarbonyl, cyano,carbamoyl, N—C₁-C₄-alkylcarbamoyl, such as N-methylcarbamoyl,N-ethylcarbamoyl or N-butylcarbamoyl, C₁-C₄-alkoxy-C₁-C₄-alkylcarbamoyl,such as N-(2-methoxyethyl)carbamoyl, C₁-C₄-alkoxy such as propyloxy,C₁-C₄-alkoxy-C₁-C₄-alkoxy such as methoxymethoxy or 2-methoxyethoxy,C₁-C₈-alkanoyloxy such as acetoxy, benzoyloxy,N—C₁-C₄-alkylcarbamoylamino, such as N-methylcarbamoylamino,C₁-C₄-alkanoylamino, such as acetylamino, C₁-C₄-alkoxycarbonylamino,such as methoxycarbonylamino, 3- to 6-membered cycloalkylcarbonylamino,such as cyclopropylcarbonylamino, C₁-C₄-alkoxy-C₁-C₄-alkanoylamino, suchas methoxyacetylamino, or 5- or 6-membered N,N-(1-oxo(loweralkylene))amino or N,N-(1-oxo-2-oxa(lower alkylene))amino, such as2-oxopyrrolidin-1-yl or 2-oxooxazolidin-3-yl,N—C₁-C₄-alkylcarbamoylamino, such as methylcarbamoylamino, R₈ ishydrogen, but may also be C₁-C₄-alkyl such as methyl, R₉ is hydrogen orhalogen and R₁₀ is C₁-C₄-alkoxy-C₁-C₄-alkyl, such asmethoxy-C₁-C₄-alkyl, ethoxy-C₁-C₄-alkyl, propyloxy-C₁-C₄-alkyl,isopropyloxy-C₁-C₄-alkyl, butyloxy-C₁-C₄-alkyl, isobutyloxy-C₁-C₄-alkyl,sec-butyloxy-C₁-C₄-alkyl or tert-butyloxy-C₁-C₄-alkyl, where C₁-C₄-alkylis, for example, ethyl, propyl or butyl, and is in particular3-methoxypropyl.
 11. Pharmaceutical preparation comprising, as an activepharmaceutical ingredient, a compound according to claim 2 in free formor as a pharmaceutically usable salt.
 12. Pharmaceutical preparationcomprising, as an active pharmaceutical ingredient, a compound accordingto claim 3 in free form or as a pharmaceutically usable salt. 13.Pharmaceutical preparation comprising, as an active pharmaceuticalingredient, a compound according to claim 4 in free form or as apharmaceutically usable salt.
 14. Pharmaceutical preparation comprising,as an active pharmaceutical ingredient, a compound according to claim 5in free form or as a pharmaceutically usable salt.